CAD & Atherosclerosis

PHILADELPHIA – Giving patients a single shot of colchicine before percutaneous coronary intervention was found to favorably impact inflammatory biomarkers linked to vascular injury, but not to lower the risk of procedure-related myocardial injury, according to results of the COLCHICINE-PCI randomized trial reported at the American Heart Association scientific sessions.

This is the first study to evaluate pre-PCI colchicine versus placebo on markers of myocardial injury and inflammation, said Binita Shah, MD, of Veterans Affairs New York Harbor Healthcare System and New York University.

“More work is needed to determine the optimal dosing and timing regimen of colchicine administration in patients undergoing PCI,” Dr. Shah said in an interview. “In this study, we saw inflammatory markers decrease around the 24-hour time point post PCI, so an earlier start to preprocedural colchicine regimen warrants further investigation.” The study found that pre-PCI colchicine attenuated increases in interleukin-6 and high-sensitivity C-reactive protein (CRP) concentrations at 24 hours post PCI, Dr. Shah said.

The results followed by a day the presentation of results from the COLCOT trial (Colchicine Cardiovascular Outcomes Trial) that showed a 23% reduction in cardiovascular events in patients with coronary disease on colchicine 0.5 mg daily vs. placebo (N Engl J Med. 2019 Nov 16. doi: 10.1056/NEJMoa1912388), as Subodh Verma, MD, PhD, of the University of Toronto noted in his discussant comments. COLCHICINE-PCI “has important implications, since patients with acute coronary syndrome often have variable biomarker responses, as biomarkers often function as acute-phase reactants in that setting.”

The COLCHICINE-PCI study of 400 patients investigated oral 1.8 mg colchicine given 1-2 hours before the patient went to the cath lab. The drug was given in a 1.2-mg dose followed an hour later by an 0.6-mg dose. Patients received placebo at the same intervals. An inflammatory biomarker substudy of 280 patients evaluated differences in plasma interleukin-6 levels at baseline and 1 hour post PCI, as well as other key biomarkers at longer intervals.

The primary outcome of PCI-related myocardial injury showed no statistically significant difference between the two groups, Dr. Shah said: 57.3% for colchicine and 64.2% for placebo (P = 0.19). The same was true of 30-day major adverse cardiovascular events, she said: 11.7% and 12.9% for the treatment and placebo groups, respectively (P = 0.82). Rates of PCI-related MI were also similar between the two groups.

However, the biomarker substudy told a different story. IL-6 levels in the treatment group were stable at 1 and 6-8 hours post PCI. “However, at 22-24 hours we see a significant attenuation in the rise of IL-6 with colchicine,” she said.

While IL-beta levels showed no deviation after PCI, the colchicine group showed a noticeable attenuation in the rise of high-sensitivity CRP levels at 22-24 hours.

“This is the first study to demonstrate that an oral load of colchicine prevents a rise of inflammatory markers in an acute-injury setting,” Dr. Shah said.

While results of the COLCOT trial affirmed a “resounding yes” for the use of colchicine in patients who’ve had a recent MI, Dr. Verma said the COLCHICINE-PCI results did not give as clear an answer.

“What about pre- or peri-PCI?” he said. “I don’t think we’re there yet, but I do think that more studies are needed that target residual inflammatory risk and potentially couple an acute loading dose with a chronic, ongoing treatment.” Results from higher-risk primary prevention studies, such as the CLEAR SYNERGY (OASIS 9) of a colchicine-spironolactone combination in patients with STEMI having PCI, are needed, he said.

Dr. Shah disclosed financial relationships with Phillips Volcano and Radux. The VA Office of Research and Development and AHA provided grant funding and Takeda Pharmaceuticals provided the drug.

SOURCE: Shah B. AHA 2019, Late Breaking Science session IV.

PHILADELPHIA – Giving patients a single shot of colchicine before percutaneous coronary intervention was found to favorably impact inflammatory biomarkers linked to vascular injury, but not to lower the risk of procedure-related myocardial injury, according to results of the COLCHICINE-PCI randomized trial reported at the American Heart Association scientific sessions.

This is the first study to evaluate pre-PCI colchicine versus placebo on markers of myocardial injury and inflammation, said Binita Shah, MD, of Veterans Affairs New York Harbor Healthcare System and New York University.

“More work is needed to determine the optimal dosing and timing regimen of colchicine administration in patients undergoing PCI,” Dr. Shah said in an interview. “In this study, we saw inflammatory markers decrease around the 24-hour time point post PCI, so an earlier start to preprocedural colchicine regimen warrants further investigation.” The study found that pre-PCI colchicine attenuated increases in interleukin-6 and high-sensitivity C-reactive protein (CRP) concentrations at 24 hours post PCI, Dr. Shah said.

The results followed by a day the presentation of results from the COLCOT trial (Colchicine Cardiovascular Outcomes Trial) that showed a 23% reduction in cardiovascular events in patients with coronary disease on colchicine 0.5 mg daily vs. placebo (N Engl J Med. 2019 Nov 16. doi: 10.1056/NEJMoa1912388), as Subodh Verma, MD, PhD, of the University of Toronto noted in his discussant comments. COLCHICINE-PCI “has important implications, since patients with acute coronary syndrome often have variable biomarker responses, as biomarkers often function as acute-phase reactants in that setting.”

The COLCHICINE-PCI study of 400 patients investigated oral 1.8 mg colchicine given 1-2 hours before the patient went to the cath lab. The drug was given in a 1.2-mg dose followed an hour later by an 0.6-mg dose. Patients received placebo at the same intervals. An inflammatory biomarker substudy of 280 patients evaluated differences in plasma interleukin-6 levels at baseline and 1 hour post PCI, as well as other key biomarkers at longer intervals.

The primary outcome of PCI-related myocardial injury showed no statistically significant difference between the two groups, Dr. Shah said: 57.3% for colchicine and 64.2% for placebo (P = 0.19). The same was true of 30-day major adverse cardiovascular events, she said: 11.7% and 12.9% for the treatment and placebo groups, respectively (P = 0.82). Rates of PCI-related MI were also similar between the two groups.

However, the biomarker substudy told a different story. IL-6 levels in the treatment group were stable at 1 and 6-8 hours post PCI. “However, at 22-24 hours we see a significant attenuation in the rise of IL-6 with colchicine,” she said.

While IL-beta levels showed no deviation after PCI, the colchicine group showed a noticeable attenuation in the rise of high-sensitivity CRP levels at 22-24 hours.

“This is the first study to demonstrate that an oral load of colchicine prevents a rise of inflammatory markers in an acute-injury setting,” Dr. Shah said.

While results of the COLCOT trial affirmed a “resounding yes” for the use of colchicine in patients who’ve had a recent MI, Dr. Verma said the COLCHICINE-PCI results did not give as clear an answer.

“What about pre- or peri-PCI?” he said. “I don’t think we’re there yet, but I do think that more studies are needed that target residual inflammatory risk and potentially couple an acute loading dose with a chronic, ongoing treatment.” Results from higher-risk primary prevention studies, such as the CLEAR SYNERGY (OASIS 9) of a colchicine-spironolactone combination in patients with STEMI having PCI, are needed, he said.

Dr. Shah disclosed financial relationships with Phillips Volcano and Radux. The VA Office of Research and Development and AHA provided grant funding and Takeda Pharmaceuticals provided the drug.

SOURCE: Shah B. AHA 2019, Late Breaking Science session IV.

PHILADELPHIA – Giving patients a single shot of colchicine before percutaneous coronary intervention was found to favorably impact inflammatory biomarkers linked to vascular injury, but not to lower the risk of procedure-related myocardial injury, according to results of the COLCHICINE-PCI randomized trial reported at the American Heart Association scientific sessions.

This is the first study to evaluate pre-PCI colchicine versus placebo on markers of myocardial injury and inflammation, said Binita Shah, MD, of Veterans Affairs New York Harbor Healthcare System and New York University.

“More work is needed to determine the optimal dosing and timing regimen of colchicine administration in patients undergoing PCI,” Dr. Shah said in an interview. “In this study, we saw inflammatory markers decrease around the 24-hour time point post PCI, so an earlier start to preprocedural colchicine regimen warrants further investigation.” The study found that pre-PCI colchicine attenuated increases in interleukin-6 and high-sensitivity C-reactive protein (CRP) concentrations at 24 hours post PCI, Dr. Shah said.

The results followed by a day the presentation of results from the COLCOT trial (Colchicine Cardiovascular Outcomes Trial) that showed a 23% reduction in cardiovascular events in patients with coronary disease on colchicine 0.5 mg daily vs. placebo (N Engl J Med. 2019 Nov 16. doi: 10.1056/NEJMoa1912388), as Subodh Verma, MD, PhD, of the University of Toronto noted in his discussant comments. COLCHICINE-PCI “has important implications, since patients with acute coronary syndrome often have variable biomarker responses, as biomarkers often function as acute-phase reactants in that setting.”

The COLCHICINE-PCI study of 400 patients investigated oral 1.8 mg colchicine given 1-2 hours before the patient went to the cath lab. The drug was given in a 1.2-mg dose followed an hour later by an 0.6-mg dose. Patients received placebo at the same intervals. An inflammatory biomarker substudy of 280 patients evaluated differences in plasma interleukin-6 levels at baseline and 1 hour post PCI, as well as other key biomarkers at longer intervals.

The primary outcome of PCI-related myocardial injury showed no statistically significant difference between the two groups, Dr. Shah said: 57.3% for colchicine and 64.2% for placebo (P = 0.19). The same was true of 30-day major adverse cardiovascular events, she said: 11.7% and 12.9% for the treatment and placebo groups, respectively (P = 0.82). Rates of PCI-related MI were also similar between the two groups.

However, the biomarker substudy told a different story. IL-6 levels in the treatment group were stable at 1 and 6-8 hours post PCI. “However, at 22-24 hours we see a significant attenuation in the rise of IL-6 with colchicine,” she said.

While IL-beta levels showed no deviation after PCI, the colchicine group showed a noticeable attenuation in the rise of high-sensitivity CRP levels at 22-24 hours.

“This is the first study to demonstrate that an oral load of colchicine prevents a rise of inflammatory markers in an acute-injury setting,” Dr. Shah said.

While results of the COLCOT trial affirmed a “resounding yes” for the use of colchicine in patients who’ve had a recent MI, Dr. Verma said the COLCHICINE-PCI results did not give as clear an answer.

“What about pre- or peri-PCI?” he said. “I don’t think we’re there yet, but I do think that more studies are needed that target residual inflammatory risk and potentially couple an acute loading dose with a chronic, ongoing treatment.” Results from higher-risk primary prevention studies, such as the CLEAR SYNERGY (OASIS 9) of a colchicine-spironolactone combination in patients with STEMI having PCI, are needed, he said.

Dr. Shah disclosed financial relationships with Phillips Volcano and Radux. The VA Office of Research and Development and AHA provided grant funding and Takeda Pharmaceuticals provided the drug.

SOURCE: Shah B. AHA 2019, Late Breaking Science session IV.

PHILADELPHIA – The overall costs of icosapent ethyl were less than placebo, and the medication reduced cardiovascular events by 30% at a cost that fits well within acceptable quality-adjusted life-year (QALY) parameters, according to a cost-effectiveness analysis of the REDUCE-IT trial.

Days before the presentation of the analysis at the American Heart Association scientific sessions, a Food and Drug Administration advisory panel unanimously recommended approval of icosapent ethyl (Vascepa) for a new indication for reducing CV event risk. Icosapent ethyl, a highly purified form of the ethyl ester of eicosapentaenoic acid derived from fish oil, received FDA approval in 2012 for treatment of triglyceride levels of at least 500 mg/dL.

“What we found here is that icosapent ethyl is a dominant strategy,” said William S. Weintraub, MD, director of outcomes research at MedStar Heart & Vascular Institute in Washington, in reporting preliminary cost-analysis findings from REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl – Intervention Trial). “It’s offering better outcomes at a lower cost.”

The dominant strategy was demonstrated by cost savings in 70% of simulations the cost-effectiveness analysis ran, Dr. Weintraub said.

“These are very impressive results,” said session moderator Seth S. Martin, MD, an internist and cardiologist at Johns Hopkins University, Baltimore. “We don’t often see dominant strategies for new drugs. This is very exciting.”

“Almost never,” Dr. Weintraub responded.

REDUCE-IT randomized 8,179 patients with a diagnosis of CVD or with diabetes and other risk factors who had been on statins and had triglycerides of 135-499 mg/dL to either 4 g of icosapent ethyl daily or placebo (N Engl J Med. 2019;380:11-22). Trial results showed the treatment group had an absolute risk reduction of 4.8% and a relative risk reduction of 25% of first CV events and a 30% relative risk reduction for total events, Dr. Weintraub said.

The analysis determined that the QALYs for icosapent ethyl versus those for placebo were 3.34 and 3.27, respectively, during the trial period and 11.61 and 11.35 over a lifetime. The mean costs for the two treatments were $27,576 and $28,205 during the trial period and $235,352 and $236,636 lifetime, respectively, Dr. Weintraub said.

An analysis of cost effectiveness showed that almost all of the estimates fell below the willingness-to-pay (WTP) threshold of $50,000 per QALY gained, Dr. Weintraub said. “In fact, some 70% plus are in what’s called quadrant two; that is, decreased cost and increased efficacy.”

The analysis also calculated the value of icosapent ethyl at three different WTP thresholds: up to $6 a day at a WTP of $50,000, up to $12 a day at $100,000, and up to $18 a day at $150,000. The analysis used the actual net pricing of $4.16 a day, Dr. Weintraub said. “That’s why we showed we have the dominant strategy,” he said.

Further cost-effectiveness analyses of the REDUCE-IT data will focus on subgroups, such as U.S. and non–U.S. patients and people with diabetes. He also emphasized the data he reported were preliminary. “We have a lot more work to do,” Dr. Weintraub said.

Dr. Weintraub reported having financial relationships with Amarin Pharma, which markets Vascepa, and AstraZeneca.

SOURCE: Weintraub WS. AHA 2019, Session FS.AOS.F1.
 

PHILADELPHIA – The overall costs of icosapent ethyl were less than placebo, and the medication reduced cardiovascular events by 30% at a cost that fits well within acceptable quality-adjusted life-year (QALY) parameters, according to a cost-effectiveness analysis of the REDUCE-IT trial.

Days before the presentation of the analysis at the American Heart Association scientific sessions, a Food and Drug Administration advisory panel unanimously recommended approval of icosapent ethyl (Vascepa) for a new indication for reducing CV event risk. Icosapent ethyl, a highly purified form of the ethyl ester of eicosapentaenoic acid derived from fish oil, received FDA approval in 2012 for treatment of triglyceride levels of at least 500 mg/dL.

“What we found here is that icosapent ethyl is a dominant strategy,” said William S. Weintraub, MD, director of outcomes research at MedStar Heart & Vascular Institute in Washington, in reporting preliminary cost-analysis findings from REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl – Intervention Trial). “It’s offering better outcomes at a lower cost.”

The dominant strategy was demonstrated by cost savings in 70% of simulations the cost-effectiveness analysis ran, Dr. Weintraub said.

“These are very impressive results,” said session moderator Seth S. Martin, MD, an internist and cardiologist at Johns Hopkins University, Baltimore. “We don’t often see dominant strategies for new drugs. This is very exciting.”

“Almost never,” Dr. Weintraub responded.

REDUCE-IT randomized 8,179 patients with a diagnosis of CVD or with diabetes and other risk factors who had been on statins and had triglycerides of 135-499 mg/dL to either 4 g of icosapent ethyl daily or placebo (N Engl J Med. 2019;380:11-22). Trial results showed the treatment group had an absolute risk reduction of 4.8% and a relative risk reduction of 25% of first CV events and a 30% relative risk reduction for total events, Dr. Weintraub said.

The analysis determined that the QALYs for icosapent ethyl versus those for placebo were 3.34 and 3.27, respectively, during the trial period and 11.61 and 11.35 over a lifetime. The mean costs for the two treatments were $27,576 and $28,205 during the trial period and $235,352 and $236,636 lifetime, respectively, Dr. Weintraub said.

An analysis of cost effectiveness showed that almost all of the estimates fell below the willingness-to-pay (WTP) threshold of $50,000 per QALY gained, Dr. Weintraub said. “In fact, some 70% plus are in what’s called quadrant two; that is, decreased cost and increased efficacy.”

The analysis also calculated the value of icosapent ethyl at three different WTP thresholds: up to $6 a day at a WTP of $50,000, up to $12 a day at $100,000, and up to $18 a day at $150,000. The analysis used the actual net pricing of $4.16 a day, Dr. Weintraub said. “That’s why we showed we have the dominant strategy,” he said.

Further cost-effectiveness analyses of the REDUCE-IT data will focus on subgroups, such as U.S. and non–U.S. patients and people with diabetes. He also emphasized the data he reported were preliminary. “We have a lot more work to do,” Dr. Weintraub said.

Dr. Weintraub reported having financial relationships with Amarin Pharma, which markets Vascepa, and AstraZeneca.

SOURCE: Weintraub WS. AHA 2019, Session FS.AOS.F1.
 

PHILADELPHIA – The overall costs of icosapent ethyl were less than placebo, and the medication reduced cardiovascular events by 30% at a cost that fits well within acceptable quality-adjusted life-year (QALY) parameters, according to a cost-effectiveness analysis of the REDUCE-IT trial.

Days before the presentation of the analysis at the American Heart Association scientific sessions, a Food and Drug Administration advisory panel unanimously recommended approval of icosapent ethyl (Vascepa) for a new indication for reducing CV event risk. Icosapent ethyl, a highly purified form of the ethyl ester of eicosapentaenoic acid derived from fish oil, received FDA approval in 2012 for treatment of triglyceride levels of at least 500 mg/dL.

“What we found here is that icosapent ethyl is a dominant strategy,” said William S. Weintraub, MD, director of outcomes research at MedStar Heart & Vascular Institute in Washington, in reporting preliminary cost-analysis findings from REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl – Intervention Trial). “It’s offering better outcomes at a lower cost.”

The dominant strategy was demonstrated by cost savings in 70% of simulations the cost-effectiveness analysis ran, Dr. Weintraub said.

“These are very impressive results,” said session moderator Seth S. Martin, MD, an internist and cardiologist at Johns Hopkins University, Baltimore. “We don’t often see dominant strategies for new drugs. This is very exciting.”

“Almost never,” Dr. Weintraub responded.

REDUCE-IT randomized 8,179 patients with a diagnosis of CVD or with diabetes and other risk factors who had been on statins and had triglycerides of 135-499 mg/dL to either 4 g of icosapent ethyl daily or placebo (N Engl J Med. 2019;380:11-22). Trial results showed the treatment group had an absolute risk reduction of 4.8% and a relative risk reduction of 25% of first CV events and a 30% relative risk reduction for total events, Dr. Weintraub said.

The analysis determined that the QALYs for icosapent ethyl versus those for placebo were 3.34 and 3.27, respectively, during the trial period and 11.61 and 11.35 over a lifetime. The mean costs for the two treatments were $27,576 and $28,205 during the trial period and $235,352 and $236,636 lifetime, respectively, Dr. Weintraub said.

An analysis of cost effectiveness showed that almost all of the estimates fell below the willingness-to-pay (WTP) threshold of $50,000 per QALY gained, Dr. Weintraub said. “In fact, some 70% plus are in what’s called quadrant two; that is, decreased cost and increased efficacy.”

The analysis also calculated the value of icosapent ethyl at three different WTP thresholds: up to $6 a day at a WTP of $50,000, up to $12 a day at $100,000, and up to $18 a day at $150,000. The analysis used the actual net pricing of $4.16 a day, Dr. Weintraub said. “That’s why we showed we have the dominant strategy,” he said.

Further cost-effectiveness analyses of the REDUCE-IT data will focus on subgroups, such as U.S. and non–U.S. patients and people with diabetes. He also emphasized the data he reported were preliminary. “We have a lot more work to do,” Dr. Weintraub said.

Dr. Weintraub reported having financial relationships with Amarin Pharma, which markets Vascepa, and AstraZeneca.

SOURCE: Weintraub WS. AHA 2019, Session FS.AOS.F1.
 

ATLANTA – Gout is associated with an increased risk of both fatal and nonfatal cardiovascular disease events, according to a large population-based health data linkage study in New Zealand.

Sharon Worcester/MDedge News

“Overall, the survival was quite good within both cohorts, but ... there is a clear and statistically significant difference in the survival between the people with gout and those without gout,” Ken Cai, MBBS, reported at the annual meeting of the American College of Rheumatology, noting that a similarly “significant and clear” difference was seen in nonfatal CVD events between the groups.

Of 968,387 individuals included in the analysis, 34,056 had gout, said Dr. Cai, a rheumatology clinical fellow at the University of Auckland (New Zealand). After adjusting for population-level estimated 5-year CVD risk for cardiovascular death, nonfatal myocardial infarction, stroke, or other vascular event, the adjusted hazard ratios were 1.20 for fatal and 1.32 for nonfatal first CVD events in patients with gout. The CVD risk score used in the analysis accounted for age, gender, ethnicity, level of social deprivation, diabetes status, previous hospitalization for atrial fibrillation, and baseline dispensing of blood pressure–lowering, lipid-lowering, and antiplatelet/anticoagulant medications.

“To allow for any other differences between the gout and nongout cohorts with respect to gender, age, ethnicity, and social deprivation, we further adjusted for these factors again, even though they had been accounted for within our CVD risk score,” he said, noting that “gout continued to demonstrate an increased adjusted hazard ratio” for fatal and nonfatal events after that adjustment (HRs, 1.40 and 1.35, respectively)

Additional analysis in the gout patients showed that CVD risk was similarly increased both in those who had been dispensed allopurinol at least once in the prior 5 years and those who had not (adjusted HRs for fatal events, 1.41 and 1.33; and for nonfatal, first CVD events, 1.34 and 1.38, respectively), and “there was no significant difference between these two groups, compared to people without gout,” he said.

Adjustment for serum urate levels in gout patients also showed similarly increased risk for fatal and nonfatal events for those with levels less than 6 mg/dL and those with levels of 6 mg/dL or greater (adjusted HRs of 1.32 and 1.42 for fatal events, and 1.27 and 1.43 for nonfatal first CVD events, respectively).

Again, no significant difference was seen in the risk of events between these two groups and those without gout, Dr. Cai said, noting that patients with no serum urate monitoring also had an increased risk of events (adjusted HR of 1.41 for fatal events and 1.29 for nonfatal, first CVD events).

Gout and hyperuricemia have previously been reported to be independent risk factors for CVD and CVD events, and urate-lowering therapy such as allopurinol have been thought to potentially be associated with reduced risk of CVD, he said, noting that the relationships are of particular concern in New Zealand, where gout affects more than 4% of the adult population.

“Maori, who are the indigenous people of New Zealand, and Pasifika people are disproportionately affected by gout; 8.5% of Maori, and 13.9% of Pasifika adults have gout,” he said, adding that an estimated one-third of Maori and Pasifika adults over age 65 years have gout.

To further assess the relationships between gout and CVD risk, he and his colleagues used validated population-level risk-prediction equations and linked National Health Identifier (NHI) data, he said.

National registries of medicines dispensing data, hospitalization, and death were linked to the Auckland/Northland regional repository of laboratory results from Jan. 1, 2012 to Dec. 31, 2016.

“We included all New Zealand residents aged 20 years or older who were in contact with publicly funded services in 2011 and were alive at the end of December, 2011,” he said, adding that those with a previous hospitalization for CVD or heart failure prior to the end of December 2011 were excluded, as were those with primary residence outside of the region for the prior 3 years and those missing predictor variable data.

Although the findings are limited by an inability to adjust for smoking status, body mass index, and blood pressure – as such data are not collected at the national level, and by the population-based nature of the study, which does not allow determination about causation, they nevertheless reinforce the association between gout and an increased estimated risk of CVD events, Dr. Cai said.

“Even after adjustment for estimated 5-year CVD risk and the additional weighting of risk factors within it, gout independently increased the hazard ratio for fatal and nonfatal events,” he said. “In our study, this effect was not ameliorated by allopurinol use or serum urate lowering to treatment target.”

Similar studies are needed in other populations, he said.

Dr. Cai reported grant support from Arthritis Australia.

sworcester@mdedge.com

SOURCE: Cai K et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 2732.

ATLANTA – Gout is associated with an increased risk of both fatal and nonfatal cardiovascular disease events, according to a large population-based health data linkage study in New Zealand.

Sharon Worcester/MDedge News

“Overall, the survival was quite good within both cohorts, but ... there is a clear and statistically significant difference in the survival between the people with gout and those without gout,” Ken Cai, MBBS, reported at the annual meeting of the American College of Rheumatology, noting that a similarly “significant and clear” difference was seen in nonfatal CVD events between the groups.

Of 968,387 individuals included in the analysis, 34,056 had gout, said Dr. Cai, a rheumatology clinical fellow at the University of Auckland (New Zealand). After adjusting for population-level estimated 5-year CVD risk for cardiovascular death, nonfatal myocardial infarction, stroke, or other vascular event, the adjusted hazard ratios were 1.20 for fatal and 1.32 for nonfatal first CVD events in patients with gout. The CVD risk score used in the analysis accounted for age, gender, ethnicity, level of social deprivation, diabetes status, previous hospitalization for atrial fibrillation, and baseline dispensing of blood pressure–lowering, lipid-lowering, and antiplatelet/anticoagulant medications.

“To allow for any other differences between the gout and nongout cohorts with respect to gender, age, ethnicity, and social deprivation, we further adjusted for these factors again, even though they had been accounted for within our CVD risk score,” he said, noting that “gout continued to demonstrate an increased adjusted hazard ratio” for fatal and nonfatal events after that adjustment (HRs, 1.40 and 1.35, respectively)

Additional analysis in the gout patients showed that CVD risk was similarly increased both in those who had been dispensed allopurinol at least once in the prior 5 years and those who had not (adjusted HRs for fatal events, 1.41 and 1.33; and for nonfatal, first CVD events, 1.34 and 1.38, respectively), and “there was no significant difference between these two groups, compared to people without gout,” he said.

Adjustment for serum urate levels in gout patients also showed similarly increased risk for fatal and nonfatal events for those with levels less than 6 mg/dL and those with levels of 6 mg/dL or greater (adjusted HRs of 1.32 and 1.42 for fatal events, and 1.27 and 1.43 for nonfatal first CVD events, respectively).

Again, no significant difference was seen in the risk of events between these two groups and those without gout, Dr. Cai said, noting that patients with no serum urate monitoring also had an increased risk of events (adjusted HR of 1.41 for fatal events and 1.29 for nonfatal, first CVD events).

Gout and hyperuricemia have previously been reported to be independent risk factors for CVD and CVD events, and urate-lowering therapy such as allopurinol have been thought to potentially be associated with reduced risk of CVD, he said, noting that the relationships are of particular concern in New Zealand, where gout affects more than 4% of the adult population.

“Maori, who are the indigenous people of New Zealand, and Pasifika people are disproportionately affected by gout; 8.5% of Maori, and 13.9% of Pasifika adults have gout,” he said, adding that an estimated one-third of Maori and Pasifika adults over age 65 years have gout.

To further assess the relationships between gout and CVD risk, he and his colleagues used validated population-level risk-prediction equations and linked National Health Identifier (NHI) data, he said.

National registries of medicines dispensing data, hospitalization, and death were linked to the Auckland/Northland regional repository of laboratory results from Jan. 1, 2012 to Dec. 31, 2016.

“We included all New Zealand residents aged 20 years or older who were in contact with publicly funded services in 2011 and were alive at the end of December, 2011,” he said, adding that those with a previous hospitalization for CVD or heart failure prior to the end of December 2011 were excluded, as were those with primary residence outside of the region for the prior 3 years and those missing predictor variable data.

Although the findings are limited by an inability to adjust for smoking status, body mass index, and blood pressure – as such data are not collected at the national level, and by the population-based nature of the study, which does not allow determination about causation, they nevertheless reinforce the association between gout and an increased estimated risk of CVD events, Dr. Cai said.

“Even after adjustment for estimated 5-year CVD risk and the additional weighting of risk factors within it, gout independently increased the hazard ratio for fatal and nonfatal events,” he said. “In our study, this effect was not ameliorated by allopurinol use or serum urate lowering to treatment target.”

Similar studies are needed in other populations, he said.

Dr. Cai reported grant support from Arthritis Australia.

sworcester@mdedge.com

SOURCE: Cai K et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 2732.

ATLANTA – Gout is associated with an increased risk of both fatal and nonfatal cardiovascular disease events, according to a large population-based health data linkage study in New Zealand.

Sharon Worcester/MDedge News

“Overall, the survival was quite good within both cohorts, but ... there is a clear and statistically significant difference in the survival between the people with gout and those without gout,” Ken Cai, MBBS, reported at the annual meeting of the American College of Rheumatology, noting that a similarly “significant and clear” difference was seen in nonfatal CVD events between the groups.

Of 968,387 individuals included in the analysis, 34,056 had gout, said Dr. Cai, a rheumatology clinical fellow at the University of Auckland (New Zealand). After adjusting for population-level estimated 5-year CVD risk for cardiovascular death, nonfatal myocardial infarction, stroke, or other vascular event, the adjusted hazard ratios were 1.20 for fatal and 1.32 for nonfatal first CVD events in patients with gout. The CVD risk score used in the analysis accounted for age, gender, ethnicity, level of social deprivation, diabetes status, previous hospitalization for atrial fibrillation, and baseline dispensing of blood pressure–lowering, lipid-lowering, and antiplatelet/anticoagulant medications.

“To allow for any other differences between the gout and nongout cohorts with respect to gender, age, ethnicity, and social deprivation, we further adjusted for these factors again, even though they had been accounted for within our CVD risk score,” he said, noting that “gout continued to demonstrate an increased adjusted hazard ratio” for fatal and nonfatal events after that adjustment (HRs, 1.40 and 1.35, respectively)

Additional analysis in the gout patients showed that CVD risk was similarly increased both in those who had been dispensed allopurinol at least once in the prior 5 years and those who had not (adjusted HRs for fatal events, 1.41 and 1.33; and for nonfatal, first CVD events, 1.34 and 1.38, respectively), and “there was no significant difference between these two groups, compared to people without gout,” he said.

Adjustment for serum urate levels in gout patients also showed similarly increased risk for fatal and nonfatal events for those with levels less than 6 mg/dL and those with levels of 6 mg/dL or greater (adjusted HRs of 1.32 and 1.42 for fatal events, and 1.27 and 1.43 for nonfatal first CVD events, respectively).

Again, no significant difference was seen in the risk of events between these two groups and those without gout, Dr. Cai said, noting that patients with no serum urate monitoring also had an increased risk of events (adjusted HR of 1.41 for fatal events and 1.29 for nonfatal, first CVD events).

Gout and hyperuricemia have previously been reported to be independent risk factors for CVD and CVD events, and urate-lowering therapy such as allopurinol have been thought to potentially be associated with reduced risk of CVD, he said, noting that the relationships are of particular concern in New Zealand, where gout affects more than 4% of the adult population.

“Maori, who are the indigenous people of New Zealand, and Pasifika people are disproportionately affected by gout; 8.5% of Maori, and 13.9% of Pasifika adults have gout,” he said, adding that an estimated one-third of Maori and Pasifika adults over age 65 years have gout.

To further assess the relationships between gout and CVD risk, he and his colleagues used validated population-level risk-prediction equations and linked National Health Identifier (NHI) data, he said.

National registries of medicines dispensing data, hospitalization, and death were linked to the Auckland/Northland regional repository of laboratory results from Jan. 1, 2012 to Dec. 31, 2016.

“We included all New Zealand residents aged 20 years or older who were in contact with publicly funded services in 2011 and were alive at the end of December, 2011,” he said, adding that those with a previous hospitalization for CVD or heart failure prior to the end of December 2011 were excluded, as were those with primary residence outside of the region for the prior 3 years and those missing predictor variable data.

Although the findings are limited by an inability to adjust for smoking status, body mass index, and blood pressure – as such data are not collected at the national level, and by the population-based nature of the study, which does not allow determination about causation, they nevertheless reinforce the association between gout and an increased estimated risk of CVD events, Dr. Cai said.

“Even after adjustment for estimated 5-year CVD risk and the additional weighting of risk factors within it, gout independently increased the hazard ratio for fatal and nonfatal events,” he said. “In our study, this effect was not ameliorated by allopurinol use or serum urate lowering to treatment target.”

Similar studies are needed in other populations, he said.

Dr. Cai reported grant support from Arthritis Australia.

sworcester@mdedge.com

SOURCE: Cai K et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 2732.

PHILADELPHIA – Treating patients to a lower LDL target after an ischemic stroke of atherosclerotic origin resulted in fewer recurrent strokes or major cardiovascular events, compared with a higher LDL goal, even though the international trial was stopped early because of lack of funding.

“In the Treat Stroke to Target [TST] trial we showed that the group of patients with an atherosclerotic stroke achieving an LDL cholesterol of less than 70 mg/dL had 22% less recurrent ischemic stroke or other major vascular events than the group achieving a LDL cholesterol between 90 and 110 mg/dL,” lead author Pierre Amarenco, MD, chairman of the department of neurology and the stroke center at Bichat Hospital in Paris, said in an interview.

“We avoided more than one in recurrence in five,” he added.

The findings of the investigator-initiated trial were reported during a late-breaking research session at the American Heart Association scientific sessions and simultaneously published online Nov. 18 in the New England Journal of Medicine (doi: 10.1056/NEJMoa1910355).

Discussant Mitchell S.V. Elkind, MD, president-elect of the American Heart Association, called the TST findings “practice confirming” of a strategy many cardiologists already follow for stroke patients.

“The TST study is only the second trial that was done in neurology for stroke prevention using statins and lipid-lowering therapy, and that’s what makes it a hopeful and real advance,” he said in an interview.

To achieve the LDL-lowering goal, two-thirds of patients received a high-dose statin therapy while the remainder received both high-dose statin and ezetimibe (Zetia, Merck). There were no significant increases in intracranial hemorrhage observed between lower- and higher-target groups.

“Now guidelines should move to recommending a target LDL cholesterol of less than 70 mg/dL in all patients with a proven ischemic stroke of atherosclerotic origin,” said Dr. Amarenco, who is also a professor of neurology at Denis Diderot Paris University.

Rare lipid study following stroke

American Heart Association/American Stroke Association guidelines recommend intense statin therapy after an atherothrombotic stroke “but no target level is given to the practitioners,” Dr. Amarenco said. “In reality, most patients receive a reduced dose of statin.”

For example, despite 70% of patients receiving a statin, the average LDL cholesterol level was 92 mg/dL in a real-world registry.

The TST trial is the first major study to evaluate treating to target LDL levels in the ischemic stroke population since the SPARCL trial in 2006. SPARCL was the first randomized, controlled clinical trial to evaluate whether daily statin therapy could reduce the risk of stroke in patients who had suffered a stroke or transient ischemic attack (TIA).

SPARCL demonstrated a 16% risk reduction with atorvastatin 80 mg daily versus placebo, and further risk reduction of 33% among those with carotid stenosis, over 5 years. There was some concern about safety for a time; post-hoc analysis showed what appeared to be an increased risk for intracranial hemorrhage with statin treatment. Subsequent analyses seemed to suggest the finding may have been a chance one, however.

For the TST study, Dr. Amarenco and colleagues enrolled participants between March 2010 and December 2018 at one of 61 centers in France. In 2015, the study expanded to include 16 sites in South Korea.

Investigators evaluated participants after an ischemic stroke or a TIA with evidence of atherosclerosis. Blood pressure, smoking cessation, and diabetes were well controlled, he said.

Dr. Amarenco and colleagues randomly assigned 1,430 participants to the low–LDL cholesterol target group, less than 70 mg/dL, and another 1,430 to a high-LDL group with a target of 100 mg/dL.

Assessments were every 6 months and up to 1 year after the last patient joined the study.

Treatment with any available statin on the market was allowed. Ezetimibe could be added on top of statin therapy as necessary. A total of 55% were statin naive at study entry.

Study stopped early

The trial was stopped in May 2019 after allocated funds ran out. At this point, researchers had 277 events to analyze, although their initial goal was to reach 385.

The primary endpoint of this event-driven trial was a composite of nonfatal stroke, nonfatal MI, and unstable angina followed by urgent coronary revascularization; TIA followed by urgent carotid revascularization; or cardiovascular death, including sudden deaths.

The endpoint was experienced by 8.5% of participants in the lower-target group versus 10.9% of those in the higher-target group. This translated to a 22% relative risk reduction (adjusted hazard ratio, 0.78; 95% confidence interval, 0.68-0.98; P =.04).

A total of 86% of participants had an ischemic stroke confirmed by brain MRI or CT scan. In this group, the relative risk reduction was 33% – “meaning that we could avoid one-third of recurrent major vascular events,” Dr. Amarenco said.

Furthermore, targeting the lower LDL levels was associated with a relative risk reduction of 40% among those with diabetes.

Secondary outcomes not significant

The investigators used hierarchical testing to compare two outcomes at a time in a prespecified order. They planned to continue this strategy until a comparison emerged as nonsignificant.

This occurred right away when their first composite secondary endpoint comparison between nonfatal MI and urgent revascularization was found to be not significantly different between groups (P = .12).

The early ending “weakened the results of the trial, and the results should be taken with caution because of that,” Dr. Amarenco said.

In addition, the number of hemorrhagic strokes did not differ significantly between groups. There were 18 of these events in the lower-target group and 13 in the higher-target cohort.

That numerical increase in intracranial hemorrhage was “driven by the Korean patients. … and that is something we will report soon,” Dr. Amarenco said.

Interestingly, the researchers also evaluated how much time participants spent within the target LDL cholesterol range, averaged by study site. They found that 53% of the lower–LDL target group, for example, was in the therapeutic range on average during the study.

When Dr. Amarenco and colleagues looked at participants who managed to spend 50%-100% in the target range, the relative risk reduction was 36%.

“So we can hypothesize that, if we had used a more potent drug like PCSK9 inhibitors to be closer to 100% in the therapeutic range, we may have had a greater effect size,” Dr. Amarenco said.

“Our results suggest that LDL cholesterol is causally related to atherosclerosis and confirm that the lower the LDL cholesterol the better,” Dr. Amarenco said.

“Future trials should explore the efficacy and safety of lowering LDL cholesterol to very low levels such as less than 55 mg/dL or even 30 mg/dL (as obtained in the FOURIER trial) by using PCSK9 inhibitors or equivalent in patients with an ischemic stroke due to atherosclerotic disease,” Dr. Amarenco said.

‘Practice-confirming’ findings

The findings are also in line with secondary analyses of the WASID (Neurology. 1995 Aug;45[8]:1488-93) and SAMMPRIS trials, which should dispel some concerns that persist about taking LDL to such low levels that it increases risk of intracerebral hemorrhage, Dr. Amarenco noted.

However, TST, he said, didn’t provide clear answers on what specific subgroups of patients with a stroke history would benefit from aggressive lipid lowering.

“What is stroke without atherosclerotic disease?” he said. “Some people say small-vessel disease is also a form of atherosclerosis, and most patients with atrial fibrillation, which is increasingly recognized as a cause of stroke, are also going to have atherosclerosis of the heart as well as the brain and blood vessels.

“Many, many stroke patients will fall into this category,” Dr. Elkind said, “and the question is, should they be treated more aggressively with lipid lowering?”

“The results of this study fit pretty nicely into the rubric of the AHA cholesterol guidelines,” said Donald M. Lloyd-Jones, MD, chairman, department of preventive medicine at Northwestern University Feinberg School of Medicine, Chicago, and chair of the AHA’s 2019 Council on Scientific Sessions Programming. Dr. Lloyd-Jones was also a member of the guideline committee.

Stroke patients are not “garden variety coronary patients,” he said. “The concern about intracerebral hemorrhage continues to be something that we wonder about: Should we be driving our stroke patients as low as our coronary patients? I think these data will certainly help us.”

Consideration for future guidelines

The study would have been more helpful if it provided more detail about the treatment regimens used, Jennifer Robinson, MD, director of the prevention intervention center, department of epidemiology, University of Iowa, said in an interview.

“What was the dose intensity of statins the patients were on?” Dr. Robinson said. “Part of our struggle has been to convince people to use high-intensity statins – get the maximum from statins that are generic now and cost saving in even very low-risk primary prevention patients.”

She said that a third of patients in TST also took ezetimibe with the statin “makes sense” because of its generic status.

Nonetheless, Dr. Robinson said, TST adds to the evidence that LDL of 100 mg/dL is not good enough, that high-intensity statin therapy is superior to a moderate regimen and that adding a nonstatin – ezetimibe in TST – can derive added benefit.

The TST findings may give guideline writers direction going forward, she said. “We really need to start thinking about the potential for net benefit from added therapy, whether it’s from intensifying LDL lowering, adding icosapent ethyl (Vascepa, Amarin), which seems to have remarkable benefits, or SGLT2 inhibitor,” she said.

“There are a lot of options,” Dr. Robinson said. “We need to have an outlook beyond just treating to target with what really is the best maximized accepted therapy.”

TST was funded primarily by French Government, but also with grants from Pfizer, Astra Zeneca and Merck. Dr. Amarenco disclosed that he is a consultant or advisor to Modest, Sanofi, Bristol-Myers Squibb, and Amgen; receives honoraria from Modest, Amgen, Kowa, Shing Poon, Kowa, Bayer, GSK, Fibrogen, and AstraZeneca. He also receives research grants from Pfizer, Astra Zeneca, Sanofi, BMS, Merck, Boston Scientific, and the French Government.

This article also appears on Medscape.com.

SOURCE: Amarenco P. ACC 2019, Late Breaking Science 6 session.

PHILADELPHIA – Treating patients to a lower LDL target after an ischemic stroke of atherosclerotic origin resulted in fewer recurrent strokes or major cardiovascular events, compared with a higher LDL goal, even though the international trial was stopped early because of lack of funding.

“In the Treat Stroke to Target [TST] trial we showed that the group of patients with an atherosclerotic stroke achieving an LDL cholesterol of less than 70 mg/dL had 22% less recurrent ischemic stroke or other major vascular events than the group achieving a LDL cholesterol between 90 and 110 mg/dL,” lead author Pierre Amarenco, MD, chairman of the department of neurology and the stroke center at Bichat Hospital in Paris, said in an interview.

“We avoided more than one in recurrence in five,” he added.

The findings of the investigator-initiated trial were reported during a late-breaking research session at the American Heart Association scientific sessions and simultaneously published online Nov. 18 in the New England Journal of Medicine (doi: 10.1056/NEJMoa1910355).

Discussant Mitchell S.V. Elkind, MD, president-elect of the American Heart Association, called the TST findings “practice confirming” of a strategy many cardiologists already follow for stroke patients.

“The TST study is only the second trial that was done in neurology for stroke prevention using statins and lipid-lowering therapy, and that’s what makes it a hopeful and real advance,” he said in an interview.

To achieve the LDL-lowering goal, two-thirds of patients received a high-dose statin therapy while the remainder received both high-dose statin and ezetimibe (Zetia, Merck). There were no significant increases in intracranial hemorrhage observed between lower- and higher-target groups.

“Now guidelines should move to recommending a target LDL cholesterol of less than 70 mg/dL in all patients with a proven ischemic stroke of atherosclerotic origin,” said Dr. Amarenco, who is also a professor of neurology at Denis Diderot Paris University.

Rare lipid study following stroke

American Heart Association/American Stroke Association guidelines recommend intense statin therapy after an atherothrombotic stroke “but no target level is given to the practitioners,” Dr. Amarenco said. “In reality, most patients receive a reduced dose of statin.”

For example, despite 70% of patients receiving a statin, the average LDL cholesterol level was 92 mg/dL in a real-world registry.

The TST trial is the first major study to evaluate treating to target LDL levels in the ischemic stroke population since the SPARCL trial in 2006. SPARCL was the first randomized, controlled clinical trial to evaluate whether daily statin therapy could reduce the risk of stroke in patients who had suffered a stroke or transient ischemic attack (TIA).

SPARCL demonstrated a 16% risk reduction with atorvastatin 80 mg daily versus placebo, and further risk reduction of 33% among those with carotid stenosis, over 5 years. There was some concern about safety for a time; post-hoc analysis showed what appeared to be an increased risk for intracranial hemorrhage with statin treatment. Subsequent analyses seemed to suggest the finding may have been a chance one, however.

For the TST study, Dr. Amarenco and colleagues enrolled participants between March 2010 and December 2018 at one of 61 centers in France. In 2015, the study expanded to include 16 sites in South Korea.

Investigators evaluated participants after an ischemic stroke or a TIA with evidence of atherosclerosis. Blood pressure, smoking cessation, and diabetes were well controlled, he said.

Dr. Amarenco and colleagues randomly assigned 1,430 participants to the low–LDL cholesterol target group, less than 70 mg/dL, and another 1,430 to a high-LDL group with a target of 100 mg/dL.

Assessments were every 6 months and up to 1 year after the last patient joined the study.

Treatment with any available statin on the market was allowed. Ezetimibe could be added on top of statin therapy as necessary. A total of 55% were statin naive at study entry.

Study stopped early

The trial was stopped in May 2019 after allocated funds ran out. At this point, researchers had 277 events to analyze, although their initial goal was to reach 385.

The primary endpoint of this event-driven trial was a composite of nonfatal stroke, nonfatal MI, and unstable angina followed by urgent coronary revascularization; TIA followed by urgent carotid revascularization; or cardiovascular death, including sudden deaths.

The endpoint was experienced by 8.5% of participants in the lower-target group versus 10.9% of those in the higher-target group. This translated to a 22% relative risk reduction (adjusted hazard ratio, 0.78; 95% confidence interval, 0.68-0.98; P =.04).

A total of 86% of participants had an ischemic stroke confirmed by brain MRI or CT scan. In this group, the relative risk reduction was 33% – “meaning that we could avoid one-third of recurrent major vascular events,” Dr. Amarenco said.

Furthermore, targeting the lower LDL levels was associated with a relative risk reduction of 40% among those with diabetes.

Secondary outcomes not significant

The investigators used hierarchical testing to compare two outcomes at a time in a prespecified order. They planned to continue this strategy until a comparison emerged as nonsignificant.

This occurred right away when their first composite secondary endpoint comparison between nonfatal MI and urgent revascularization was found to be not significantly different between groups (P = .12).

The early ending “weakened the results of the trial, and the results should be taken with caution because of that,” Dr. Amarenco said.

In addition, the number of hemorrhagic strokes did not differ significantly between groups. There were 18 of these events in the lower-target group and 13 in the higher-target cohort.

That numerical increase in intracranial hemorrhage was “driven by the Korean patients. … and that is something we will report soon,” Dr. Amarenco said.

Interestingly, the researchers also evaluated how much time participants spent within the target LDL cholesterol range, averaged by study site. They found that 53% of the lower–LDL target group, for example, was in the therapeutic range on average during the study.

When Dr. Amarenco and colleagues looked at participants who managed to spend 50%-100% in the target range, the relative risk reduction was 36%.

“So we can hypothesize that, if we had used a more potent drug like PCSK9 inhibitors to be closer to 100% in the therapeutic range, we may have had a greater effect size,” Dr. Amarenco said.

“Our results suggest that LDL cholesterol is causally related to atherosclerosis and confirm that the lower the LDL cholesterol the better,” Dr. Amarenco said.

“Future trials should explore the efficacy and safety of lowering LDL cholesterol to very low levels such as less than 55 mg/dL or even 30 mg/dL (as obtained in the FOURIER trial) by using PCSK9 inhibitors or equivalent in patients with an ischemic stroke due to atherosclerotic disease,” Dr. Amarenco said.

‘Practice-confirming’ findings

The findings are also in line with secondary analyses of the WASID (Neurology. 1995 Aug;45[8]:1488-93) and SAMMPRIS trials, which should dispel some concerns that persist about taking LDL to such low levels that it increases risk of intracerebral hemorrhage, Dr. Amarenco noted.

However, TST, he said, didn’t provide clear answers on what specific subgroups of patients with a stroke history would benefit from aggressive lipid lowering.

“What is stroke without atherosclerotic disease?” he said. “Some people say small-vessel disease is also a form of atherosclerosis, and most patients with atrial fibrillation, which is increasingly recognized as a cause of stroke, are also going to have atherosclerosis of the heart as well as the brain and blood vessels.

“Many, many stroke patients will fall into this category,” Dr. Elkind said, “and the question is, should they be treated more aggressively with lipid lowering?”

“The results of this study fit pretty nicely into the rubric of the AHA cholesterol guidelines,” said Donald M. Lloyd-Jones, MD, chairman, department of preventive medicine at Northwestern University Feinberg School of Medicine, Chicago, and chair of the AHA’s 2019 Council on Scientific Sessions Programming. Dr. Lloyd-Jones was also a member of the guideline committee.

Stroke patients are not “garden variety coronary patients,” he said. “The concern about intracerebral hemorrhage continues to be something that we wonder about: Should we be driving our stroke patients as low as our coronary patients? I think these data will certainly help us.”

Consideration for future guidelines

The study would have been more helpful if it provided more detail about the treatment regimens used, Jennifer Robinson, MD, director of the prevention intervention center, department of epidemiology, University of Iowa, said in an interview.

“What was the dose intensity of statins the patients were on?” Dr. Robinson said. “Part of our struggle has been to convince people to use high-intensity statins – get the maximum from statins that are generic now and cost saving in even very low-risk primary prevention patients.”

She said that a third of patients in TST also took ezetimibe with the statin “makes sense” because of its generic status.

Nonetheless, Dr. Robinson said, TST adds to the evidence that LDL of 100 mg/dL is not good enough, that high-intensity statin therapy is superior to a moderate regimen and that adding a nonstatin – ezetimibe in TST – can derive added benefit.

The TST findings may give guideline writers direction going forward, she said. “We really need to start thinking about the potential for net benefit from added therapy, whether it’s from intensifying LDL lowering, adding icosapent ethyl (Vascepa, Amarin), which seems to have remarkable benefits, or SGLT2 inhibitor,” she said.

“There are a lot of options,” Dr. Robinson said. “We need to have an outlook beyond just treating to target with what really is the best maximized accepted therapy.”

TST was funded primarily by French Government, but also with grants from Pfizer, Astra Zeneca and Merck. Dr. Amarenco disclosed that he is a consultant or advisor to Modest, Sanofi, Bristol-Myers Squibb, and Amgen; receives honoraria from Modest, Amgen, Kowa, Shing Poon, Kowa, Bayer, GSK, Fibrogen, and AstraZeneca. He also receives research grants from Pfizer, Astra Zeneca, Sanofi, BMS, Merck, Boston Scientific, and the French Government.

This article also appears on Medscape.com.

SOURCE: Amarenco P. ACC 2019, Late Breaking Science 6 session.

PHILADELPHIA – Treating patients to a lower LDL target after an ischemic stroke of atherosclerotic origin resulted in fewer recurrent strokes or major cardiovascular events, compared with a higher LDL goal, even though the international trial was stopped early because of lack of funding.

“In the Treat Stroke to Target [TST] trial we showed that the group of patients with an atherosclerotic stroke achieving an LDL cholesterol of less than 70 mg/dL had 22% less recurrent ischemic stroke or other major vascular events than the group achieving a LDL cholesterol between 90 and 110 mg/dL,” lead author Pierre Amarenco, MD, chairman of the department of neurology and the stroke center at Bichat Hospital in Paris, said in an interview.

“We avoided more than one in recurrence in five,” he added.

The findings of the investigator-initiated trial were reported during a late-breaking research session at the American Heart Association scientific sessions and simultaneously published online Nov. 18 in the New England Journal of Medicine (doi: 10.1056/NEJMoa1910355).

Discussant Mitchell S.V. Elkind, MD, president-elect of the American Heart Association, called the TST findings “practice confirming” of a strategy many cardiologists already follow for stroke patients.

“The TST study is only the second trial that was done in neurology for stroke prevention using statins and lipid-lowering therapy, and that’s what makes it a hopeful and real advance,” he said in an interview.

To achieve the LDL-lowering goal, two-thirds of patients received a high-dose statin therapy while the remainder received both high-dose statin and ezetimibe (Zetia, Merck). There were no significant increases in intracranial hemorrhage observed between lower- and higher-target groups.

“Now guidelines should move to recommending a target LDL cholesterol of less than 70 mg/dL in all patients with a proven ischemic stroke of atherosclerotic origin,” said Dr. Amarenco, who is also a professor of neurology at Denis Diderot Paris University.

Rare lipid study following stroke

American Heart Association/American Stroke Association guidelines recommend intense statin therapy after an atherothrombotic stroke “but no target level is given to the practitioners,” Dr. Amarenco said. “In reality, most patients receive a reduced dose of statin.”

For example, despite 70% of patients receiving a statin, the average LDL cholesterol level was 92 mg/dL in a real-world registry.

The TST trial is the first major study to evaluate treating to target LDL levels in the ischemic stroke population since the SPARCL trial in 2006. SPARCL was the first randomized, controlled clinical trial to evaluate whether daily statin therapy could reduce the risk of stroke in patients who had suffered a stroke or transient ischemic attack (TIA).

SPARCL demonstrated a 16% risk reduction with atorvastatin 80 mg daily versus placebo, and further risk reduction of 33% among those with carotid stenosis, over 5 years. There was some concern about safety for a time; post-hoc analysis showed what appeared to be an increased risk for intracranial hemorrhage with statin treatment. Subsequent analyses seemed to suggest the finding may have been a chance one, however.

For the TST study, Dr. Amarenco and colleagues enrolled participants between March 2010 and December 2018 at one of 61 centers in France. In 2015, the study expanded to include 16 sites in South Korea.

Investigators evaluated participants after an ischemic stroke or a TIA with evidence of atherosclerosis. Blood pressure, smoking cessation, and diabetes were well controlled, he said.

Dr. Amarenco and colleagues randomly assigned 1,430 participants to the low–LDL cholesterol target group, less than 70 mg/dL, and another 1,430 to a high-LDL group with a target of 100 mg/dL.

Assessments were every 6 months and up to 1 year after the last patient joined the study.

Treatment with any available statin on the market was allowed. Ezetimibe could be added on top of statin therapy as necessary. A total of 55% were statin naive at study entry.

Study stopped early

The trial was stopped in May 2019 after allocated funds ran out. At this point, researchers had 277 events to analyze, although their initial goal was to reach 385.

The primary endpoint of this event-driven trial was a composite of nonfatal stroke, nonfatal MI, and unstable angina followed by urgent coronary revascularization; TIA followed by urgent carotid revascularization; or cardiovascular death, including sudden deaths.

The endpoint was experienced by 8.5% of participants in the lower-target group versus 10.9% of those in the higher-target group. This translated to a 22% relative risk reduction (adjusted hazard ratio, 0.78; 95% confidence interval, 0.68-0.98; P =.04).

A total of 86% of participants had an ischemic stroke confirmed by brain MRI or CT scan. In this group, the relative risk reduction was 33% – “meaning that we could avoid one-third of recurrent major vascular events,” Dr. Amarenco said.

Furthermore, targeting the lower LDL levels was associated with a relative risk reduction of 40% among those with diabetes.

Secondary outcomes not significant

The investigators used hierarchical testing to compare two outcomes at a time in a prespecified order. They planned to continue this strategy until a comparison emerged as nonsignificant.

This occurred right away when their first composite secondary endpoint comparison between nonfatal MI and urgent revascularization was found to be not significantly different between groups (P = .12).

The early ending “weakened the results of the trial, and the results should be taken with caution because of that,” Dr. Amarenco said.

In addition, the number of hemorrhagic strokes did not differ significantly between groups. There were 18 of these events in the lower-target group and 13 in the higher-target cohort.

That numerical increase in intracranial hemorrhage was “driven by the Korean patients. … and that is something we will report soon,” Dr. Amarenco said.

Interestingly, the researchers also evaluated how much time participants spent within the target LDL cholesterol range, averaged by study site. They found that 53% of the lower–LDL target group, for example, was in the therapeutic range on average during the study.

When Dr. Amarenco and colleagues looked at participants who managed to spend 50%-100% in the target range, the relative risk reduction was 36%.

“So we can hypothesize that, if we had used a more potent drug like PCSK9 inhibitors to be closer to 100% in the therapeutic range, we may have had a greater effect size,” Dr. Amarenco said.

“Our results suggest that LDL cholesterol is causally related to atherosclerosis and confirm that the lower the LDL cholesterol the better,” Dr. Amarenco said.

“Future trials should explore the efficacy and safety of lowering LDL cholesterol to very low levels such as less than 55 mg/dL or even 30 mg/dL (as obtained in the FOURIER trial) by using PCSK9 inhibitors or equivalent in patients with an ischemic stroke due to atherosclerotic disease,” Dr. Amarenco said.

‘Practice-confirming’ findings

The findings are also in line with secondary analyses of the WASID (Neurology. 1995 Aug;45[8]:1488-93) and SAMMPRIS trials, which should dispel some concerns that persist about taking LDL to such low levels that it increases risk of intracerebral hemorrhage, Dr. Amarenco noted.

However, TST, he said, didn’t provide clear answers on what specific subgroups of patients with a stroke history would benefit from aggressive lipid lowering.

“What is stroke without atherosclerotic disease?” he said. “Some people say small-vessel disease is also a form of atherosclerosis, and most patients with atrial fibrillation, which is increasingly recognized as a cause of stroke, are also going to have atherosclerosis of the heart as well as the brain and blood vessels.

“Many, many stroke patients will fall into this category,” Dr. Elkind said, “and the question is, should they be treated more aggressively with lipid lowering?”

“The results of this study fit pretty nicely into the rubric of the AHA cholesterol guidelines,” said Donald M. Lloyd-Jones, MD, chairman, department of preventive medicine at Northwestern University Feinberg School of Medicine, Chicago, and chair of the AHA’s 2019 Council on Scientific Sessions Programming. Dr. Lloyd-Jones was also a member of the guideline committee.

Stroke patients are not “garden variety coronary patients,” he said. “The concern about intracerebral hemorrhage continues to be something that we wonder about: Should we be driving our stroke patients as low as our coronary patients? I think these data will certainly help us.”

Consideration for future guidelines

The study would have been more helpful if it provided more detail about the treatment regimens used, Jennifer Robinson, MD, director of the prevention intervention center, department of epidemiology, University of Iowa, said in an interview.

“What was the dose intensity of statins the patients were on?” Dr. Robinson said. “Part of our struggle has been to convince people to use high-intensity statins – get the maximum from statins that are generic now and cost saving in even very low-risk primary prevention patients.”

She said that a third of patients in TST also took ezetimibe with the statin “makes sense” because of its generic status.

Nonetheless, Dr. Robinson said, TST adds to the evidence that LDL of 100 mg/dL is not good enough, that high-intensity statin therapy is superior to a moderate regimen and that adding a nonstatin – ezetimibe in TST – can derive added benefit.

The TST findings may give guideline writers direction going forward, she said. “We really need to start thinking about the potential for net benefit from added therapy, whether it’s from intensifying LDL lowering, adding icosapent ethyl (Vascepa, Amarin), which seems to have remarkable benefits, or SGLT2 inhibitor,” she said.

“There are a lot of options,” Dr. Robinson said. “We need to have an outlook beyond just treating to target with what really is the best maximized accepted therapy.”

TST was funded primarily by French Government, but also with grants from Pfizer, Astra Zeneca and Merck. Dr. Amarenco disclosed that he is a consultant or advisor to Modest, Sanofi, Bristol-Myers Squibb, and Amgen; receives honoraria from Modest, Amgen, Kowa, Shing Poon, Kowa, Bayer, GSK, Fibrogen, and AstraZeneca. He also receives research grants from Pfizer, Astra Zeneca, Sanofi, BMS, Merck, Boston Scientific, and the French Government.

This article also appears on Medscape.com.

SOURCE: Amarenco P. ACC 2019, Late Breaking Science 6 session.

PHILADELPHIA – The eagerly awaited results of the ISCHEMIA trial – the largest-ever randomized trial of an initial invasive versus conservative management strategy for patients with stable ischemic heart disease – were emphatically declared practice-changing by interventional cardiologists and noninterventionalists alike at the American Heart Association scientific sessions.

Bruce Jancin/MDedge News

At a median 3.3 years of follow-up of 5,179 participants with baseline moderate or severe ischemia at 320 sites in 37 countries in ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches), an initial invasive strategy accompanied by optimal medical therapy (OMT) didn’t reduce the risk of the primary composite endpoint of cardiovascular death, MI, hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest, compared with a conservative strategy of OMT alone. The rates at 4 years were 15.5% with the conservative strategy and 13.3% with the invasive strategy, reported study chair Judith S. Hochman, MD, professor of medicine and senior associate dean for clinical sciences at New York University.

Nor was there a significant between-group difference in the major secondary endpoint of cardiovascular death or MI: 13.9% with the conservative strategy, 11.7% with invasive management.

“The probability of at least a 10% benefit of the invasive strategy on all-cause mortality was less than 10%, based on a prespecified Bayesian analysis,” she added.

Prior to enrollment and randomization, CT angiography was routinely performed to rule out left main coronary artery disease.

Fifty-four percent of participants in the National Heart, Lung, and Blood Institute–funded trial had severe ischemia on a baseline noninvasive stress test. To the investigators’ surprise, patients with more severe ischemia or more extensive multivessel involvement didn’t do better with the invasive approach.

Almost a quarter (23%) of patients in the conservative management group crossed over to revascularization within 4 years.
 

Quality-of-life results

An invasive strategy did result in significantly greater improvement in angina control and quality of life, as measured using the Seattle Angina Questionnaire, than OMT alone in patients who had angina at least once a month at baseline.

“We have 100% confidence that there is a treatment benefit associated with an invasive approach early as well as late after randomization,” said John A. Spertus, MD, coprincipal investigator for the ISCHEMIA quality of life analysis.

Indeed, he calculated that, for patients with weekly angina, the number needed to treat with revascularization instead of OMT alone for one to be angina-free at 3 months was three.

However, in the 35% of ISCHEMIA participants who reported no angina within the past month at baseline, the invasive strategy offered no quality of life advantage, he added.

“I really think we need to hit ‘pause’ on asymptomatic revascularization. I just don’t see any benefit in patients without symptoms, left main disease excluded,” commented Dr. Spertus, director of health outcomes research at St. Luke’s Mid-America Heart Institute and professor of medicine at the University of Missouri, Kansas City.

The reaction

ISCHEMIA addressed a key clinical issue that’s long been surrounded by equipoise because of a paucity of high-quality data. As such, it was deemed worthy of its own AHA Late-Breaking Science session. The assembled discussants agreed the results will change their clinical practice.

Bruce Jancin/MDedge News

Bruce Jancin/MDedge News

bjancin@mdedge.com

SOURCE: Hochman JS. AHA late breaker.

PHILADELPHIA – The eagerly awaited results of the ISCHEMIA trial – the largest-ever randomized trial of an initial invasive versus conservative management strategy for patients with stable ischemic heart disease – were emphatically declared practice-changing by interventional cardiologists and noninterventionalists alike at the American Heart Association scientific sessions.

Bruce Jancin/MDedge News

At a median 3.3 years of follow-up of 5,179 participants with baseline moderate or severe ischemia at 320 sites in 37 countries in ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches), an initial invasive strategy accompanied by optimal medical therapy (OMT) didn’t reduce the risk of the primary composite endpoint of cardiovascular death, MI, hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest, compared with a conservative strategy of OMT alone. The rates at 4 years were 15.5% with the conservative strategy and 13.3% with the invasive strategy, reported study chair Judith S. Hochman, MD, professor of medicine and senior associate dean for clinical sciences at New York University.

Nor was there a significant between-group difference in the major secondary endpoint of cardiovascular death or MI: 13.9% with the conservative strategy, 11.7% with invasive management.

“The probability of at least a 10% benefit of the invasive strategy on all-cause mortality was less than 10%, based on a prespecified Bayesian analysis,” she added.

Prior to enrollment and randomization, CT angiography was routinely performed to rule out left main coronary artery disease.

Fifty-four percent of participants in the National Heart, Lung, and Blood Institute–funded trial had severe ischemia on a baseline noninvasive stress test. To the investigators’ surprise, patients with more severe ischemia or more extensive multivessel involvement didn’t do better with the invasive approach.

Almost a quarter (23%) of patients in the conservative management group crossed over to revascularization within 4 years.
 

Quality-of-life results

An invasive strategy did result in significantly greater improvement in angina control and quality of life, as measured using the Seattle Angina Questionnaire, than OMT alone in patients who had angina at least once a month at baseline.

“We have 100% confidence that there is a treatment benefit associated with an invasive approach early as well as late after randomization,” said John A. Spertus, MD, coprincipal investigator for the ISCHEMIA quality of life analysis.

Indeed, he calculated that, for patients with weekly angina, the number needed to treat with revascularization instead of OMT alone for one to be angina-free at 3 months was three.

However, in the 35% of ISCHEMIA participants who reported no angina within the past month at baseline, the invasive strategy offered no quality of life advantage, he added.

“I really think we need to hit ‘pause’ on asymptomatic revascularization. I just don’t see any benefit in patients without symptoms, left main disease excluded,” commented Dr. Spertus, director of health outcomes research at St. Luke’s Mid-America Heart Institute and professor of medicine at the University of Missouri, Kansas City.

The reaction

ISCHEMIA addressed a key clinical issue that’s long been surrounded by equipoise because of a paucity of high-quality data. As such, it was deemed worthy of its own AHA Late-Breaking Science session. The assembled discussants agreed the results will change their clinical practice.

Bruce Jancin/MDedge News

Bruce Jancin/MDedge News

bjancin@mdedge.com

SOURCE: Hochman JS. AHA late breaker.

PHILADELPHIA – The eagerly awaited results of the ISCHEMIA trial – the largest-ever randomized trial of an initial invasive versus conservative management strategy for patients with stable ischemic heart disease – were emphatically declared practice-changing by interventional cardiologists and noninterventionalists alike at the American Heart Association scientific sessions.

Bruce Jancin/MDedge News

At a median 3.3 years of follow-up of 5,179 participants with baseline moderate or severe ischemia at 320 sites in 37 countries in ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches), an initial invasive strategy accompanied by optimal medical therapy (OMT) didn’t reduce the risk of the primary composite endpoint of cardiovascular death, MI, hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest, compared with a conservative strategy of OMT alone. The rates at 4 years were 15.5% with the conservative strategy and 13.3% with the invasive strategy, reported study chair Judith S. Hochman, MD, professor of medicine and senior associate dean for clinical sciences at New York University.

Nor was there a significant between-group difference in the major secondary endpoint of cardiovascular death or MI: 13.9% with the conservative strategy, 11.7% with invasive management.

“The probability of at least a 10% benefit of the invasive strategy on all-cause mortality was less than 10%, based on a prespecified Bayesian analysis,” she added.

Prior to enrollment and randomization, CT angiography was routinely performed to rule out left main coronary artery disease.

Fifty-four percent of participants in the National Heart, Lung, and Blood Institute–funded trial had severe ischemia on a baseline noninvasive stress test. To the investigators’ surprise, patients with more severe ischemia or more extensive multivessel involvement didn’t do better with the invasive approach.

Almost a quarter (23%) of patients in the conservative management group crossed over to revascularization within 4 years.
 

Quality-of-life results

An invasive strategy did result in significantly greater improvement in angina control and quality of life, as measured using the Seattle Angina Questionnaire, than OMT alone in patients who had angina at least once a month at baseline.

“We have 100% confidence that there is a treatment benefit associated with an invasive approach early as well as late after randomization,” said John A. Spertus, MD, coprincipal investigator for the ISCHEMIA quality of life analysis.

Indeed, he calculated that, for patients with weekly angina, the number needed to treat with revascularization instead of OMT alone for one to be angina-free at 3 months was three.

However, in the 35% of ISCHEMIA participants who reported no angina within the past month at baseline, the invasive strategy offered no quality of life advantage, he added.

“I really think we need to hit ‘pause’ on asymptomatic revascularization. I just don’t see any benefit in patients without symptoms, left main disease excluded,” commented Dr. Spertus, director of health outcomes research at St. Luke’s Mid-America Heart Institute and professor of medicine at the University of Missouri, Kansas City.

The reaction

ISCHEMIA addressed a key clinical issue that’s long been surrounded by equipoise because of a paucity of high-quality data. As such, it was deemed worthy of its own AHA Late-Breaking Science session. The assembled discussants agreed the results will change their clinical practice.

Bruce Jancin/MDedge News

Bruce Jancin/MDedge News

bjancin@mdedge.com

SOURCE: Hochman JS. AHA late breaker.

Dobutamine stress echocardiography could be used to predict which patients with single-vessel stable coronary artery disease are most likely to benefit from percutaneous coronary intervention, according to secondary analysis of data from the ORBITA trial.

In a study to be presented at the American Heart Association scientific sessions on Nov. 16, researchers outline the results of a stress-echo stratification of patients who participated in the Objective Randomized Blinded Investigation with Optimal Medical Therapy of Angioplasty in Stable Angina (ORBITA) trial.

©Thinkstock

Patients with a prerandomization stress echo score at or above 1 were three times more likely to have a lower angina frequency score with PCI than with placebo (odds ratio, 3.18; 95% confidence interval, 1.38, 7.34; P = .007). They were also more than four times more likely to be free from angina with PCI compared to placebo (OR, 4.62; 95% CI, 1.70, 12.60; P = .003).

“We have previously found that there is a clear relationship between invasive physiology and stress echo score but no relationship between invasive physiology and placebo-controlled symptom improvement,” the authors wrote. “The present analysis shows that there is clear evidence of a relationship between ischemia on stress echo and the placebo-controlled efficacy of PCI on frequency of angina.”

The analysis, however, found no detectable interaction between prerandomization stress echo score and the effect of PCI on physical limitation score, quality of life, Canadian Cardiovascular Society angina class score, or treadmill time.

The mean prerandomization stress echo score was 1.56 in the PCI arm and 1.61 in the placebo arm.

The study also looked at the relationship between prerandomization stress echo score and fractional flow reserve. This revealed that, as the stress echo score increased with a greater number of ischemia myocardial segments, the fractional flow reserve value decreased, pointing to a greater degree of ischemia. Researchers also noted that as the stress echo score became larger, the instantaneous wave-free ratio also decreased significantly.

“This stress echo-stratified analysis shows the link between stress-induced myocardial wall motion abnormalities and patient-reported angina frequency,” the authors wrote. “The greater the ischemia on [dobutamine stress echocardiography], the greater the placebo-controlled angina relief from PCI.”

The study was funded by grants from the National Institute for Health Research Imperial Biomedical Research Centre, Foundation for Circulatory Health, Imperial College Healthcare Charity, and in-kind support from Philips Volcano. Two authors declared patents relating to technology used in the study and three declared consultancies, speakers’ fees, and research grants from Philips Volcano. No other conflicts of interest were declared.

SOURCE: Al-Lamee R et al. Circulation. 2019 Nov 11. doi: doi.org/10.1161/CIRCULATIONAHA.119.042918.

Dobutamine stress echocardiography could be used to predict which patients with single-vessel stable coronary artery disease are most likely to benefit from percutaneous coronary intervention, according to secondary analysis of data from the ORBITA trial.

In a study to be presented at the American Heart Association scientific sessions on Nov. 16, researchers outline the results of a stress-echo stratification of patients who participated in the Objective Randomized Blinded Investigation with Optimal Medical Therapy of Angioplasty in Stable Angina (ORBITA) trial.

©Thinkstock

Patients with a prerandomization stress echo score at or above 1 were three times more likely to have a lower angina frequency score with PCI than with placebo (odds ratio, 3.18; 95% confidence interval, 1.38, 7.34; P = .007). They were also more than four times more likely to be free from angina with PCI compared to placebo (OR, 4.62; 95% CI, 1.70, 12.60; P = .003).

“We have previously found that there is a clear relationship between invasive physiology and stress echo score but no relationship between invasive physiology and placebo-controlled symptom improvement,” the authors wrote. “The present analysis shows that there is clear evidence of a relationship between ischemia on stress echo and the placebo-controlled efficacy of PCI on frequency of angina.”

The analysis, however, found no detectable interaction between prerandomization stress echo score and the effect of PCI on physical limitation score, quality of life, Canadian Cardiovascular Society angina class score, or treadmill time.

The mean prerandomization stress echo score was 1.56 in the PCI arm and 1.61 in the placebo arm.

The study also looked at the relationship between prerandomization stress echo score and fractional flow reserve. This revealed that, as the stress echo score increased with a greater number of ischemia myocardial segments, the fractional flow reserve value decreased, pointing to a greater degree of ischemia. Researchers also noted that as the stress echo score became larger, the instantaneous wave-free ratio also decreased significantly.

“This stress echo-stratified analysis shows the link between stress-induced myocardial wall motion abnormalities and patient-reported angina frequency,” the authors wrote. “The greater the ischemia on [dobutamine stress echocardiography], the greater the placebo-controlled angina relief from PCI.”

The study was funded by grants from the National Institute for Health Research Imperial Biomedical Research Centre, Foundation for Circulatory Health, Imperial College Healthcare Charity, and in-kind support from Philips Volcano. Two authors declared patents relating to technology used in the study and three declared consultancies, speakers’ fees, and research grants from Philips Volcano. No other conflicts of interest were declared.

SOURCE: Al-Lamee R et al. Circulation. 2019 Nov 11. doi: doi.org/10.1161/CIRCULATIONAHA.119.042918.

Dobutamine stress echocardiography could be used to predict which patients with single-vessel stable coronary artery disease are most likely to benefit from percutaneous coronary intervention, according to secondary analysis of data from the ORBITA trial.

In a study to be presented at the American Heart Association scientific sessions on Nov. 16, researchers outline the results of a stress-echo stratification of patients who participated in the Objective Randomized Blinded Investigation with Optimal Medical Therapy of Angioplasty in Stable Angina (ORBITA) trial.

©Thinkstock

Patients with a prerandomization stress echo score at or above 1 were three times more likely to have a lower angina frequency score with PCI than with placebo (odds ratio, 3.18; 95% confidence interval, 1.38, 7.34; P = .007). They were also more than four times more likely to be free from angina with PCI compared to placebo (OR, 4.62; 95% CI, 1.70, 12.60; P = .003).

“We have previously found that there is a clear relationship between invasive physiology and stress echo score but no relationship between invasive physiology and placebo-controlled symptom improvement,” the authors wrote. “The present analysis shows that there is clear evidence of a relationship between ischemia on stress echo and the placebo-controlled efficacy of PCI on frequency of angina.”

The analysis, however, found no detectable interaction between prerandomization stress echo score and the effect of PCI on physical limitation score, quality of life, Canadian Cardiovascular Society angina class score, or treadmill time.

The mean prerandomization stress echo score was 1.56 in the PCI arm and 1.61 in the placebo arm.

The study also looked at the relationship between prerandomization stress echo score and fractional flow reserve. This revealed that, as the stress echo score increased with a greater number of ischemia myocardial segments, the fractional flow reserve value decreased, pointing to a greater degree of ischemia. Researchers also noted that as the stress echo score became larger, the instantaneous wave-free ratio also decreased significantly.

“This stress echo-stratified analysis shows the link between stress-induced myocardial wall motion abnormalities and patient-reported angina frequency,” the authors wrote. “The greater the ischemia on [dobutamine stress echocardiography], the greater the placebo-controlled angina relief from PCI.”

The study was funded by grants from the National Institute for Health Research Imperial Biomedical Research Centre, Foundation for Circulatory Health, Imperial College Healthcare Charity, and in-kind support from Philips Volcano. Two authors declared patents relating to technology used in the study and three declared consultancies, speakers’ fees, and research grants from Philips Volcano. No other conflicts of interest were declared.

SOURCE: Al-Lamee R et al. Circulation. 2019 Nov 11. doi: doi.org/10.1161/CIRCULATIONAHA.119.042918.

Icosapent ethyl, a highly purified form of the ethyl ester of eicosapentaenoic acid, received unanimous backing from a Food and Drug Administration advisory panel for a new indication for reducing cardiovascular event risk.

Icosapent ethyl (Vascepa) received initial agency approval in 2012 for the indication of cutting triglyceride levels once they reached at least 500 mg/dL.

The target patient population for this new, cardiovascular-event protection role will reflect some or all of the types of patients enrolled in REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial), which tested icosapent ethyl in 8,179 patients with either established cardiovascular disease or diabetes and at least one additional cardiovascular disease risk factor. This study provided the bulk of the data considered by the FDA panel.

REDUCE-IT showed that, during a median of 4.9 years, patients who received icosapent ethyl had a statistically significant 25% relative risk reduction in the trial’s primary, composite endpoint (New Engl J Med. 2019 Jan 3;380[1]:11-22).

Icosapent ethyl “appeared effective and safe,” and would be a “useful, new, added agent for treating patients” like those enrolled in the trial, said Kenneth D. Burman, MD, professor and chief of endocrinology at Medstar Washington (D.C.) Hospital Center and chair of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee.

The advisory panel members appeared uniformly comfortable with recommending that the FDA add a cardiovascular disease indication based on the REDUCE-IT findings.

But while they agreed that icosapent ethyl should receive some type of indication for cardiovascular event reduction, the committee split over which patients the indication should include. Specifically, they diverged on the issue of primary prevention.

Some said that the patient enrollment that produced a positive result in REDUCE-IT should not be retrospectively subdivided, while others said that combining secondary- and primary-prevention patients in a single large trial inappropriately lumped together patients who would be better considered separately.

Committee members also expressed uncertainty over the appropriate triglyceride level to warrant treatment. The REDUCE-IT trial was designed to enroll patients with triglycerides of 135 mg/dL or greater, but several panel members suggested that, for labeling, the threshold should be at least 150 mg/dL, or even 200 mg/dL.

Safety was another aspect that generated a lot of panel discussion throughout their day-long discussion, with particular focus on a signal of a small but concerning increased rate of incident atrial fibrillation among patients who received icosapent ethyl, as well as a small but nearly significant increase in the rate of serious bleeds.

Further analyses presented during the meeting showed that an increased bleeding rate linked with icosapent ethyl was focused in patients who concurrently received one or more antiplatelet drugs or an anticoagulant.

However, panel members rejected the notion that these safety concerns warranted a boxed warning, agreeing that it could be managed with appropriate labeling information.

Clinician reaction

Clinicians who manage these types of patients viewed the prospect of an expanded indication for icosapent ethyl as an important advance.

The REDUCE-IT results by themselves “were convincing” for patients with established cardiovascular disease without need for a confirmatory trial, Robert H. Eckel, MD, an endocrinologist and professor of medicine at the University of Colorado at Denver, Aurora, said in an interview. But he remained unconvinced about efficacy for primary-prevention patients, or even for secondary-prevention patients with a triglyceride level below 150 mg/dL.

“Icosapent ethyl will clearly be a mainstay for managing high-risk patients. It gives us another treatment option,” Yehuda Handelsman, MD, an endocrinologist and medical director and principal investigator of the Metabolic Institute of America in Tarzana, Calif., said in an interview. “I do not see the atrial fibrillation or bleeding effects as reasons not to approve this drug. It should be a precaution. Overall, icosapent ethyl is one of the easier drugs for patients to take.”

Dr. Handelsman said it would be unethical to run a confirmatory trial and randomize patients to placebo. “Another trial makes no sense,” he said.

But the data from REDUCE-IT were “not as convincing” for primary-prevention patients, suggesting a need for caution about using icosapent ethyl for patients without established cardiovascular disease, Paul S. Jellinger, MD, an endocrinologist in Fort Lauderdale, Fla., said in an interview.

Cost-effectiveness

An analysis of the cost-effectiveness of icosapent ethyl as used in REDUCE-IT showed that the drug fell into the rare category of being a “dominant” treatment, meaning that it both improved patient outcomes and reduced medical costs. William S. Weintraub, MD, will report findings from this analysis on Nov. 16, 2019, at the annual scientific sessions of the American Heart Association.

The analysis used a wholesale acquisition cost for a 1-day dosage of icosapent ethyl of $4.16, derived from a commercial source for prescription-drug pricing and actual hospitalization costs for the patients in the trial.

Based on the REDUCE-IT outcomes, treatment with icosapent ethyl was linked with a boost in quality-adjusted life-years that extrapolated to an average 0.26 increase during the full lifetime of REDUCE-IT participants, at a cost that averaged $1,284 less per treated patient over their lifetime, according to Dr. Weintraub, director of Outcomes Research at Medstar Washington Hospital Center, Washington.

Although the 0.26 lifetime increase in quality-adjusted life-years may sound modest, “in the cost-effectiveness world, 0.26 is actually significant,” Dr. Weintraub said. He also highlighted how unusual it is to find a patented drug that improves quality of life and longevity while also saving money.

“I know of no other on-patent, branded pharmaceutical that is dominant,” he said.

Off-patent pharmaceuticals, like statins, can be quite inexpensive and may also be dominant, he noted. Being dominant for cost-effectiveness means that icosapent ethyl “provides good value and is worth what we pay for it, well within social thresholds of willingness to pay,” Dr. Weintraub said.

REDUCE-IT was sponsored by Amarin, the company that markets icosapent ethyl (Vascepa). Dr. Burman has received research funding from AstraZeneca, Eisai, and IBSA. Dr. Eckel has received personal fees from Kowa Pharmaceuticals, Merck, Novartis, and Sanofi/Regeneron, as well as research funding from Endece, Ionis Pharmaceuticals, and UniQure. Dr. Handelsman has been a consultant to and received research funding from Amarin and several other companies. Dr. Jellinger has been a speaker on behalf of Amarin, Amgen, and Regeneron. Dr. Weintraub has received honoraria and research support from Amarin, and honoraria from AstraZeneca.

mzoler@mdedge.com

Icosapent ethyl, a highly purified form of the ethyl ester of eicosapentaenoic acid, received unanimous backing from a Food and Drug Administration advisory panel for a new indication for reducing cardiovascular event risk.

Icosapent ethyl (Vascepa) received initial agency approval in 2012 for the indication of cutting triglyceride levels once they reached at least 500 mg/dL.

The target patient population for this new, cardiovascular-event protection role will reflect some or all of the types of patients enrolled in REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial), which tested icosapent ethyl in 8,179 patients with either established cardiovascular disease or diabetes and at least one additional cardiovascular disease risk factor. This study provided the bulk of the data considered by the FDA panel.

REDUCE-IT showed that, during a median of 4.9 years, patients who received icosapent ethyl had a statistically significant 25% relative risk reduction in the trial’s primary, composite endpoint (New Engl J Med. 2019 Jan 3;380[1]:11-22).

Icosapent ethyl “appeared effective and safe,” and would be a “useful, new, added agent for treating patients” like those enrolled in the trial, said Kenneth D. Burman, MD, professor and chief of endocrinology at Medstar Washington (D.C.) Hospital Center and chair of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee.

The advisory panel members appeared uniformly comfortable with recommending that the FDA add a cardiovascular disease indication based on the REDUCE-IT findings.

But while they agreed that icosapent ethyl should receive some type of indication for cardiovascular event reduction, the committee split over which patients the indication should include. Specifically, they diverged on the issue of primary prevention.

Some said that the patient enrollment that produced a positive result in REDUCE-IT should not be retrospectively subdivided, while others said that combining secondary- and primary-prevention patients in a single large trial inappropriately lumped together patients who would be better considered separately.

Committee members also expressed uncertainty over the appropriate triglyceride level to warrant treatment. The REDUCE-IT trial was designed to enroll patients with triglycerides of 135 mg/dL or greater, but several panel members suggested that, for labeling, the threshold should be at least 150 mg/dL, or even 200 mg/dL.

Safety was another aspect that generated a lot of panel discussion throughout their day-long discussion, with particular focus on a signal of a small but concerning increased rate of incident atrial fibrillation among patients who received icosapent ethyl, as well as a small but nearly significant increase in the rate of serious bleeds.

Further analyses presented during the meeting showed that an increased bleeding rate linked with icosapent ethyl was focused in patients who concurrently received one or more antiplatelet drugs or an anticoagulant.

However, panel members rejected the notion that these safety concerns warranted a boxed warning, agreeing that it could be managed with appropriate labeling information.

Clinician reaction

Clinicians who manage these types of patients viewed the prospect of an expanded indication for icosapent ethyl as an important advance.

The REDUCE-IT results by themselves “were convincing” for patients with established cardiovascular disease without need for a confirmatory trial, Robert H. Eckel, MD, an endocrinologist and professor of medicine at the University of Colorado at Denver, Aurora, said in an interview. But he remained unconvinced about efficacy for primary-prevention patients, or even for secondary-prevention patients with a triglyceride level below 150 mg/dL.

“Icosapent ethyl will clearly be a mainstay for managing high-risk patients. It gives us another treatment option,” Yehuda Handelsman, MD, an endocrinologist and medical director and principal investigator of the Metabolic Institute of America in Tarzana, Calif., said in an interview. “I do not see the atrial fibrillation or bleeding effects as reasons not to approve this drug. It should be a precaution. Overall, icosapent ethyl is one of the easier drugs for patients to take.”

Dr. Handelsman said it would be unethical to run a confirmatory trial and randomize patients to placebo. “Another trial makes no sense,” he said.

But the data from REDUCE-IT were “not as convincing” for primary-prevention patients, suggesting a need for caution about using icosapent ethyl for patients without established cardiovascular disease, Paul S. Jellinger, MD, an endocrinologist in Fort Lauderdale, Fla., said in an interview.

Cost-effectiveness

An analysis of the cost-effectiveness of icosapent ethyl as used in REDUCE-IT showed that the drug fell into the rare category of being a “dominant” treatment, meaning that it both improved patient outcomes and reduced medical costs. William S. Weintraub, MD, will report findings from this analysis on Nov. 16, 2019, at the annual scientific sessions of the American Heart Association.

The analysis used a wholesale acquisition cost for a 1-day dosage of icosapent ethyl of $4.16, derived from a commercial source for prescription-drug pricing and actual hospitalization costs for the patients in the trial.

Based on the REDUCE-IT outcomes, treatment with icosapent ethyl was linked with a boost in quality-adjusted life-years that extrapolated to an average 0.26 increase during the full lifetime of REDUCE-IT participants, at a cost that averaged $1,284 less per treated patient over their lifetime, according to Dr. Weintraub, director of Outcomes Research at Medstar Washington Hospital Center, Washington.

Although the 0.26 lifetime increase in quality-adjusted life-years may sound modest, “in the cost-effectiveness world, 0.26 is actually significant,” Dr. Weintraub said. He also highlighted how unusual it is to find a patented drug that improves quality of life and longevity while also saving money.

“I know of no other on-patent, branded pharmaceutical that is dominant,” he said.

Off-patent pharmaceuticals, like statins, can be quite inexpensive and may also be dominant, he noted. Being dominant for cost-effectiveness means that icosapent ethyl “provides good value and is worth what we pay for it, well within social thresholds of willingness to pay,” Dr. Weintraub said.

REDUCE-IT was sponsored by Amarin, the company that markets icosapent ethyl (Vascepa). Dr. Burman has received research funding from AstraZeneca, Eisai, and IBSA. Dr. Eckel has received personal fees from Kowa Pharmaceuticals, Merck, Novartis, and Sanofi/Regeneron, as well as research funding from Endece, Ionis Pharmaceuticals, and UniQure. Dr. Handelsman has been a consultant to and received research funding from Amarin and several other companies. Dr. Jellinger has been a speaker on behalf of Amarin, Amgen, and Regeneron. Dr. Weintraub has received honoraria and research support from Amarin, and honoraria from AstraZeneca.

mzoler@mdedge.com

Icosapent ethyl, a highly purified form of the ethyl ester of eicosapentaenoic acid, received unanimous backing from a Food and Drug Administration advisory panel for a new indication for reducing cardiovascular event risk.

Icosapent ethyl (Vascepa) received initial agency approval in 2012 for the indication of cutting triglyceride levels once they reached at least 500 mg/dL.

The target patient population for this new, cardiovascular-event protection role will reflect some or all of the types of patients enrolled in REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial), which tested icosapent ethyl in 8,179 patients with either established cardiovascular disease or diabetes and at least one additional cardiovascular disease risk factor. This study provided the bulk of the data considered by the FDA panel.

REDUCE-IT showed that, during a median of 4.9 years, patients who received icosapent ethyl had a statistically significant 25% relative risk reduction in the trial’s primary, composite endpoint (New Engl J Med. 2019 Jan 3;380[1]:11-22).

Icosapent ethyl “appeared effective and safe,” and would be a “useful, new, added agent for treating patients” like those enrolled in the trial, said Kenneth D. Burman, MD, professor and chief of endocrinology at Medstar Washington (D.C.) Hospital Center and chair of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee.

The advisory panel members appeared uniformly comfortable with recommending that the FDA add a cardiovascular disease indication based on the REDUCE-IT findings.

But while they agreed that icosapent ethyl should receive some type of indication for cardiovascular event reduction, the committee split over which patients the indication should include. Specifically, they diverged on the issue of primary prevention.

Some said that the patient enrollment that produced a positive result in REDUCE-IT should not be retrospectively subdivided, while others said that combining secondary- and primary-prevention patients in a single large trial inappropriately lumped together patients who would be better considered separately.

Committee members also expressed uncertainty over the appropriate triglyceride level to warrant treatment. The REDUCE-IT trial was designed to enroll patients with triglycerides of 135 mg/dL or greater, but several panel members suggested that, for labeling, the threshold should be at least 150 mg/dL, or even 200 mg/dL.

Safety was another aspect that generated a lot of panel discussion throughout their day-long discussion, with particular focus on a signal of a small but concerning increased rate of incident atrial fibrillation among patients who received icosapent ethyl, as well as a small but nearly significant increase in the rate of serious bleeds.

Further analyses presented during the meeting showed that an increased bleeding rate linked with icosapent ethyl was focused in patients who concurrently received one or more antiplatelet drugs or an anticoagulant.

However, panel members rejected the notion that these safety concerns warranted a boxed warning, agreeing that it could be managed with appropriate labeling information.

Clinician reaction

Clinicians who manage these types of patients viewed the prospect of an expanded indication for icosapent ethyl as an important advance.

The REDUCE-IT results by themselves “were convincing” for patients with established cardiovascular disease without need for a confirmatory trial, Robert H. Eckel, MD, an endocrinologist and professor of medicine at the University of Colorado at Denver, Aurora, said in an interview. But he remained unconvinced about efficacy for primary-prevention patients, or even for secondary-prevention patients with a triglyceride level below 150 mg/dL.

“Icosapent ethyl will clearly be a mainstay for managing high-risk patients. It gives us another treatment option,” Yehuda Handelsman, MD, an endocrinologist and medical director and principal investigator of the Metabolic Institute of America in Tarzana, Calif., said in an interview. “I do not see the atrial fibrillation or bleeding effects as reasons not to approve this drug. It should be a precaution. Overall, icosapent ethyl is one of the easier drugs for patients to take.”

Dr. Handelsman said it would be unethical to run a confirmatory trial and randomize patients to placebo. “Another trial makes no sense,” he said.

But the data from REDUCE-IT were “not as convincing” for primary-prevention patients, suggesting a need for caution about using icosapent ethyl for patients without established cardiovascular disease, Paul S. Jellinger, MD, an endocrinologist in Fort Lauderdale, Fla., said in an interview.

Cost-effectiveness

An analysis of the cost-effectiveness of icosapent ethyl as used in REDUCE-IT showed that the drug fell into the rare category of being a “dominant” treatment, meaning that it both improved patient outcomes and reduced medical costs. William S. Weintraub, MD, will report findings from this analysis on Nov. 16, 2019, at the annual scientific sessions of the American Heart Association.

The analysis used a wholesale acquisition cost for a 1-day dosage of icosapent ethyl of $4.16, derived from a commercial source for prescription-drug pricing and actual hospitalization costs for the patients in the trial.

Based on the REDUCE-IT outcomes, treatment with icosapent ethyl was linked with a boost in quality-adjusted life-years that extrapolated to an average 0.26 increase during the full lifetime of REDUCE-IT participants, at a cost that averaged $1,284 less per treated patient over their lifetime, according to Dr. Weintraub, director of Outcomes Research at Medstar Washington Hospital Center, Washington.

Although the 0.26 lifetime increase in quality-adjusted life-years may sound modest, “in the cost-effectiveness world, 0.26 is actually significant,” Dr. Weintraub said. He also highlighted how unusual it is to find a patented drug that improves quality of life and longevity while also saving money.

“I know of no other on-patent, branded pharmaceutical that is dominant,” he said.

Off-patent pharmaceuticals, like statins, can be quite inexpensive and may also be dominant, he noted. Being dominant for cost-effectiveness means that icosapent ethyl “provides good value and is worth what we pay for it, well within social thresholds of willingness to pay,” Dr. Weintraub said.

REDUCE-IT was sponsored by Amarin, the company that markets icosapent ethyl (Vascepa). Dr. Burman has received research funding from AstraZeneca, Eisai, and IBSA. Dr. Eckel has received personal fees from Kowa Pharmaceuticals, Merck, Novartis, and Sanofi/Regeneron, as well as research funding from Endece, Ionis Pharmaceuticals, and UniQure. Dr. Handelsman has been a consultant to and received research funding from Amarin and several other companies. Dr. Jellinger has been a speaker on behalf of Amarin, Amgen, and Regeneron. Dr. Weintraub has received honoraria and research support from Amarin, and honoraria from AstraZeneca.

mzoler@mdedge.com

When added to maximally tolerated statin therapy, bempedoic acid reduced LDL cholesterol by more than 15%, compared with placebo, Anne C. Goldberg, MD, and colleagues reported in JAMA.

The prodrug also improved non-HDL cholesterol, total cholesterol, apolipoprotein B, and C-reactive protein in a group of patients who remained at high risk of cardiovascular events despite maximally tolerated statin treatment, said Dr. Goldberg of Washington University, St. Louis, and coauthors in reporting the results of CLEAR Wisdom (Evaluation of Long-Term Efficacy of Bempedoic Acid [ETC-1002] in Patients With Hyperlipidemia at High Cardiovascular Risk).

The prodrug bempedoic acid works differently than most statins. In the liver, the drug activates into bempedoyl-CoA. It interrupts ATP-citrate lyase, an enzyme critical to the main statin target, 3-hydroxy-3-methylglutaryl-CoA reductase. Although it reduces cholesterol synthesis in the liver, bempedoic acid isn’t active in skeletal muscle, unlike statins.

The 52-week placebo-controlled trial included 2,300 patients enrolled at 91 international sites. All of them had atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both. They were randomized 2:1 to bempedoic acid 180 mg daily or placebo. Patients were a mean of 64 years old, with a mean LDL cholesterol level of 120.4 mg/dL. Most (89.6%) were receiving statin therapy, with 53% receiving high-intensity treatment.

The primary endpoint was change in LDL cholesterol. Secondary measures included overall lipid changes and changes in lipoprotein and biomarkers of cardiovascular disease.

After 12 weeks, patients taking bempedoic acid experienced significantly lowered LDL cholesterol, compared with those taking placebo (–15% vs. 2.4%; between-group difference, 17.4%). The key secondary endpoints were also positive, including non–LDL cholesterol (–10.8% vs. 2.3%), total cholesterol (–9.9% vs. 1.3%), apolipoprotein B (–9.3% vs 3.7%), and high-sensitivity C-reactive protein (median, –18.7% vs –9.4%)

Most patients in both groups (about 70%) experienced at least one adverse event. However, the majority of those (77.6%) were not related to the study drug. Most were mild to moderate and included myalgia (1% vs. 0.8%), increased aspartate aminotransferase level (0.6% vs. 0%), and arthralgia (0.6% vs. 0%).

Serious adverse events occurred in 19.8% of patients, with three possibly related to bempedoic acid. These were ulcerative colitis and ischemic stroke in the bempedoic acid group and upper abdominal pain in the placebo group.

Eight fatalities occurred during the CLEAR Wisdom. There were single cases of cardiac arrest, coronary artery arteriosclerosis, acute poisoning with carbon dioxide, myocardial infarction, and septic shock related to a prescheduled abdominal surgical procedure. One patient in the active group died from an unknown cause.

Four events in the bempedoic acid group and two events in the placebo group were cardiovascular deaths.

New or worsening diabetes developed in approximately 7% of each group, and less than 3% of those taking bempedoic acid developed gout or increased blood uric acid, as was the case for less than 1% of patients taking placebo.

In May, the Food and Drug Administration accepted a New Drug Application from Esperion for bempedoic acid. A response is expected in February 2020.

Dr. Goldberg reporter receiving research grants/support from Amgen, Amarin, Pfizer, Regeneron, Sanofi, IONIS, Novartis, and Merck and serving as a consultant for Esperion, Novartis, Akcea, OptumRX, 23andMe, Sanofi/Regeneron, and Merck.

msullivan@mdedge.com

SOURCE: Goldberg AC et al. JAMA. 2019 Nov 12;322:1780-8.

When added to maximally tolerated statin therapy, bempedoic acid reduced LDL cholesterol by more than 15%, compared with placebo, Anne C. Goldberg, MD, and colleagues reported in JAMA.

The prodrug also improved non-HDL cholesterol, total cholesterol, apolipoprotein B, and C-reactive protein in a group of patients who remained at high risk of cardiovascular events despite maximally tolerated statin treatment, said Dr. Goldberg of Washington University, St. Louis, and coauthors in reporting the results of CLEAR Wisdom (Evaluation of Long-Term Efficacy of Bempedoic Acid [ETC-1002] in Patients With Hyperlipidemia at High Cardiovascular Risk).

The prodrug bempedoic acid works differently than most statins. In the liver, the drug activates into bempedoyl-CoA. It interrupts ATP-citrate lyase, an enzyme critical to the main statin target, 3-hydroxy-3-methylglutaryl-CoA reductase. Although it reduces cholesterol synthesis in the liver, bempedoic acid isn’t active in skeletal muscle, unlike statins.

The 52-week placebo-controlled trial included 2,300 patients enrolled at 91 international sites. All of them had atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both. They were randomized 2:1 to bempedoic acid 180 mg daily or placebo. Patients were a mean of 64 years old, with a mean LDL cholesterol level of 120.4 mg/dL. Most (89.6%) were receiving statin therapy, with 53% receiving high-intensity treatment.

The primary endpoint was change in LDL cholesterol. Secondary measures included overall lipid changes and changes in lipoprotein and biomarkers of cardiovascular disease.

After 12 weeks, patients taking bempedoic acid experienced significantly lowered LDL cholesterol, compared with those taking placebo (–15% vs. 2.4%; between-group difference, 17.4%). The key secondary endpoints were also positive, including non–LDL cholesterol (–10.8% vs. 2.3%), total cholesterol (–9.9% vs. 1.3%), apolipoprotein B (–9.3% vs 3.7%), and high-sensitivity C-reactive protein (median, –18.7% vs –9.4%)

Most patients in both groups (about 70%) experienced at least one adverse event. However, the majority of those (77.6%) were not related to the study drug. Most were mild to moderate and included myalgia (1% vs. 0.8%), increased aspartate aminotransferase level (0.6% vs. 0%), and arthralgia (0.6% vs. 0%).

Serious adverse events occurred in 19.8% of patients, with three possibly related to bempedoic acid. These were ulcerative colitis and ischemic stroke in the bempedoic acid group and upper abdominal pain in the placebo group.

Eight fatalities occurred during the CLEAR Wisdom. There were single cases of cardiac arrest, coronary artery arteriosclerosis, acute poisoning with carbon dioxide, myocardial infarction, and septic shock related to a prescheduled abdominal surgical procedure. One patient in the active group died from an unknown cause.

Four events in the bempedoic acid group and two events in the placebo group were cardiovascular deaths.

New or worsening diabetes developed in approximately 7% of each group, and less than 3% of those taking bempedoic acid developed gout or increased blood uric acid, as was the case for less than 1% of patients taking placebo.

In May, the Food and Drug Administration accepted a New Drug Application from Esperion for bempedoic acid. A response is expected in February 2020.

Dr. Goldberg reporter receiving research grants/support from Amgen, Amarin, Pfizer, Regeneron, Sanofi, IONIS, Novartis, and Merck and serving as a consultant for Esperion, Novartis, Akcea, OptumRX, 23andMe, Sanofi/Regeneron, and Merck.

msullivan@mdedge.com

SOURCE: Goldberg AC et al. JAMA. 2019 Nov 12;322:1780-8.

When added to maximally tolerated statin therapy, bempedoic acid reduced LDL cholesterol by more than 15%, compared with placebo, Anne C. Goldberg, MD, and colleagues reported in JAMA.

The prodrug also improved non-HDL cholesterol, total cholesterol, apolipoprotein B, and C-reactive protein in a group of patients who remained at high risk of cardiovascular events despite maximally tolerated statin treatment, said Dr. Goldberg of Washington University, St. Louis, and coauthors in reporting the results of CLEAR Wisdom (Evaluation of Long-Term Efficacy of Bempedoic Acid [ETC-1002] in Patients With Hyperlipidemia at High Cardiovascular Risk).

The prodrug bempedoic acid works differently than most statins. In the liver, the drug activates into bempedoyl-CoA. It interrupts ATP-citrate lyase, an enzyme critical to the main statin target, 3-hydroxy-3-methylglutaryl-CoA reductase. Although it reduces cholesterol synthesis in the liver, bempedoic acid isn’t active in skeletal muscle, unlike statins.

The 52-week placebo-controlled trial included 2,300 patients enrolled at 91 international sites. All of them had atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both. They were randomized 2:1 to bempedoic acid 180 mg daily or placebo. Patients were a mean of 64 years old, with a mean LDL cholesterol level of 120.4 mg/dL. Most (89.6%) were receiving statin therapy, with 53% receiving high-intensity treatment.

The primary endpoint was change in LDL cholesterol. Secondary measures included overall lipid changes and changes in lipoprotein and biomarkers of cardiovascular disease.

After 12 weeks, patients taking bempedoic acid experienced significantly lowered LDL cholesterol, compared with those taking placebo (–15% vs. 2.4%; between-group difference, 17.4%). The key secondary endpoints were also positive, including non–LDL cholesterol (–10.8% vs. 2.3%), total cholesterol (–9.9% vs. 1.3%), apolipoprotein B (–9.3% vs 3.7%), and high-sensitivity C-reactive protein (median, –18.7% vs –9.4%)

Most patients in both groups (about 70%) experienced at least one adverse event. However, the majority of those (77.6%) were not related to the study drug. Most were mild to moderate and included myalgia (1% vs. 0.8%), increased aspartate aminotransferase level (0.6% vs. 0%), and arthralgia (0.6% vs. 0%).

Serious adverse events occurred in 19.8% of patients, with three possibly related to bempedoic acid. These were ulcerative colitis and ischemic stroke in the bempedoic acid group and upper abdominal pain in the placebo group.

Eight fatalities occurred during the CLEAR Wisdom. There were single cases of cardiac arrest, coronary artery arteriosclerosis, acute poisoning with carbon dioxide, myocardial infarction, and septic shock related to a prescheduled abdominal surgical procedure. One patient in the active group died from an unknown cause.

Four events in the bempedoic acid group and two events in the placebo group were cardiovascular deaths.

New or worsening diabetes developed in approximately 7% of each group, and less than 3% of those taking bempedoic acid developed gout or increased blood uric acid, as was the case for less than 1% of patients taking placebo.

In May, the Food and Drug Administration accepted a New Drug Application from Esperion for bempedoic acid. A response is expected in February 2020.

Dr. Goldberg reporter receiving research grants/support from Amgen, Amarin, Pfizer, Regeneron, Sanofi, IONIS, Novartis, and Merck and serving as a consultant for Esperion, Novartis, Akcea, OptumRX, 23andMe, Sanofi/Regeneron, and Merck.

msullivan@mdedge.com

SOURCE: Goldberg AC et al. JAMA. 2019 Nov 12;322:1780-8.

PARIS – Over the course of years and decades, lower LDL cholesterol levels and lower systolic blood pressure can reduce the lifetime risk of cardiovascular disease by up to 80%, according to a new study.

SilverV/thinkstockphotos

“What we found is that lifetime exposure to the combination of lower LDL and lower systolic blood pressure is associated with independent, additive, and dose-dependent effects on the lifetime risk of cardiovascular disease,” said the study’s senior author, Brian Ference, MD, speaking at the annual congress of the European Society of Cardiology. “The data seem to confirm that most cardiovascular events are preventable, and suggest that most cardiovascular events can be prevented, with prolonged exposure to modestly lower LDL cholesterol and systolic blood pressure.”

Any reduction of LDL-C and systolic blood pressure (SBP), in any combination, was associated with a lower lifetime risk of cardiovascular disease (CVD) in the study, which took advantage of the United Kingdom’s large Biobank to identify individuals with genetically lower LDL-C and blood pressure levels. The relationship was dose-dependent and showed a log-linear relationship to the combined absolute LDL-C and SBP differences, said Dr. Ference, professor and executive director of the Centre for Naturally Randomised Trials at the University of Cambridge, England.

The results validate current guidelines that focus on a lifetime approach to cardiovascular risk reduction and support a focus on therapeutic lifestyle interventions for individuals at all levels of risk for cardiovascular events, said Dr. Ference. He foresees the results shaping new risk-estimating algorithms and informing the next round of prevention guidelines.

Previous studies had suggested that long-term exposure to lower levels of LDL-C and lower systolic blood pressure reduced cardiovascular risk, but the association hadn’t been fully quantified. Ideally, said Dr. Ference, the question would be answered by a long-term randomized controlled trial, but it would be decades before meaningful data would accrue, and such a trial is unlikely to be conducted.

Using data from 438,952 Biobank participants, Dr. Ference and coinvestigators sought to quantify the association between LDL-C, systolic blood pressure, and atherosclerotic CVD. Taking advantage of genetic variants known to be associated with both lower LDL-C and lower systolic blood pressure, the researchers constructed a “natural randomization” trial. This trial design is also known as Mendelian randomization.

First, the entire study population was randomized into those with exome variants associated with higher or lower LDL-C, which resulted in a mean 15-mg/dL difference between the arms. Then, each LDL-C arm was randomized into groups with exome variants associated with higher or lower SBP, resulting in a difference of 2.9-3 mm Hg between the blood pressure arms within each LDL arm. This randomization yielded a reference group, a group with lower LDL-C, a group with lower SBP, and a group with lower LDL-C and SBP.

For the total population, the mean LDL-C was 138 mg/dL, and the mean SBP was 137.8 mm Hg.

A total of 24,980 participants had coronary revascularization, a nonfatal myocardial infarction (MI), or coronary death – the composite primary outcome measure of major coronary events.

“What we found is that long-term exposure to the combination of 1 mmol/L [about 39 mg/dL] lower LDL and 10 mm/Hg lower blood pressure is associated with an 80% lifetime reduction in risk of cardiovascular events, a 75% reduction in the risk of MI, and 68% reduction in the long-term risk of cardiovascular death,” said Dr. Ference.

By breaking participants out into separate quartiles of LDL-C and SBP levels, and examining outcomes for each quartile independently, Dr. Ference and collaborators were able to ascertain that the salutary effects of lower LDL-C and SBP were independent of each other.

Looking at individual cardiovascular outcomes, “The effect of combined exposure to both lower LDL and lower systolic blood pressure appear to be quite similar across multiple composite cardiovascular outcomes,” said Dr. Ference; benefit was seen in risk of MI, stroke, and other vascular events.

Plotting out the amount of risk reduction against the genetic scores for LDL-C and SBP reduction showed a proportional relationship that was logarithmically linear. “These large proportional reductions in risk really suggest that, for LDL, systolic blood pressure, and their combination, the benefit really depends both on the magnitude and the duration of the exposure,” said Dr. Ference. The effect was seen regardless of age, gender, body mass index, and diabetes status; being a smoker slightly attenuated the effects of LDL-C and SBP.

The mean participant age was 65 years, and women made up 54% of the study population. Aside from lipid values and systolic blood pressure, there were no significant between-group differences.

From these findings, what message can clinicians take to their patients? “Benefit is a much greater motivator, rather than the nebulous concept of risk,” said Dr. Ference. “So if we begin to crystallize and give an estimate of how much someone can benefit – either from adhering to a healthy lifestyle, with specific goals for LDL and blood pressure reductions, or from encouraging them to remain compliant with their therapies, achieving those corresponding goals – we can quantify their expected clinical benefit and encourage them to invest in their health over the long term.”

Dr. Ference said that the actual mechanism by which lipids and blood pressure are lowered matters less than the amount and duration of lowering: “These data are really agnostic as to the mechanism by which either blood pressure or LDL – or apo-B–containing lipoproteins generally – and blood pressure are reduced. It really suggests that whatever mechanism by which an individual person can most effectively lower their LDL and blood pressure, that’s the best one for that person, if they can maintain that over time.”

Dr. Ference reported financial relationships, including research contracts, consulting arrangements, receipt of royalties, and being an owner or stockholder of more than a dozen pharmaceutical companies. The study was funded by the United Kingdom’s National Institute of Health Research and Medical Research Council, and by the British Heart Foundation.

koakes@mdedge.com

SOURCE: Ference B. et al. ESC Congress 2019, Hot Line Session 3.

PARIS – Over the course of years and decades, lower LDL cholesterol levels and lower systolic blood pressure can reduce the lifetime risk of cardiovascular disease by up to 80%, according to a new study.

SilverV/thinkstockphotos

“What we found is that lifetime exposure to the combination of lower LDL and lower systolic blood pressure is associated with independent, additive, and dose-dependent effects on the lifetime risk of cardiovascular disease,” said the study’s senior author, Brian Ference, MD, speaking at the annual congress of the European Society of Cardiology. “The data seem to confirm that most cardiovascular events are preventable, and suggest that most cardiovascular events can be prevented, with prolonged exposure to modestly lower LDL cholesterol and systolic blood pressure.”

Any reduction of LDL-C and systolic blood pressure (SBP), in any combination, was associated with a lower lifetime risk of cardiovascular disease (CVD) in the study, which took advantage of the United Kingdom’s large Biobank to identify individuals with genetically lower LDL-C and blood pressure levels. The relationship was dose-dependent and showed a log-linear relationship to the combined absolute LDL-C and SBP differences, said Dr. Ference, professor and executive director of the Centre for Naturally Randomised Trials at the University of Cambridge, England.

The results validate current guidelines that focus on a lifetime approach to cardiovascular risk reduction and support a focus on therapeutic lifestyle interventions for individuals at all levels of risk for cardiovascular events, said Dr. Ference. He foresees the results shaping new risk-estimating algorithms and informing the next round of prevention guidelines.

Previous studies had suggested that long-term exposure to lower levels of LDL-C and lower systolic blood pressure reduced cardiovascular risk, but the association hadn’t been fully quantified. Ideally, said Dr. Ference, the question would be answered by a long-term randomized controlled trial, but it would be decades before meaningful data would accrue, and such a trial is unlikely to be conducted.

Using data from 438,952 Biobank participants, Dr. Ference and coinvestigators sought to quantify the association between LDL-C, systolic blood pressure, and atherosclerotic CVD. Taking advantage of genetic variants known to be associated with both lower LDL-C and lower systolic blood pressure, the researchers constructed a “natural randomization” trial. This trial design is also known as Mendelian randomization.

First, the entire study population was randomized into those with exome variants associated with higher or lower LDL-C, which resulted in a mean 15-mg/dL difference between the arms. Then, each LDL-C arm was randomized into groups with exome variants associated with higher or lower SBP, resulting in a difference of 2.9-3 mm Hg between the blood pressure arms within each LDL arm. This randomization yielded a reference group, a group with lower LDL-C, a group with lower SBP, and a group with lower LDL-C and SBP.

For the total population, the mean LDL-C was 138 mg/dL, and the mean SBP was 137.8 mm Hg.

A total of 24,980 participants had coronary revascularization, a nonfatal myocardial infarction (MI), or coronary death – the composite primary outcome measure of major coronary events.

“What we found is that long-term exposure to the combination of 1 mmol/L [about 39 mg/dL] lower LDL and 10 mm/Hg lower blood pressure is associated with an 80% lifetime reduction in risk of cardiovascular events, a 75% reduction in the risk of MI, and 68% reduction in the long-term risk of cardiovascular death,” said Dr. Ference.

By breaking participants out into separate quartiles of LDL-C and SBP levels, and examining outcomes for each quartile independently, Dr. Ference and collaborators were able to ascertain that the salutary effects of lower LDL-C and SBP were independent of each other.

Looking at individual cardiovascular outcomes, “The effect of combined exposure to both lower LDL and lower systolic blood pressure appear to be quite similar across multiple composite cardiovascular outcomes,” said Dr. Ference; benefit was seen in risk of MI, stroke, and other vascular events.

Plotting out the amount of risk reduction against the genetic scores for LDL-C and SBP reduction showed a proportional relationship that was logarithmically linear. “These large proportional reductions in risk really suggest that, for LDL, systolic blood pressure, and their combination, the benefit really depends both on the magnitude and the duration of the exposure,” said Dr. Ference. The effect was seen regardless of age, gender, body mass index, and diabetes status; being a smoker slightly attenuated the effects of LDL-C and SBP.

The mean participant age was 65 years, and women made up 54% of the study population. Aside from lipid values and systolic blood pressure, there were no significant between-group differences.

From these findings, what message can clinicians take to their patients? “Benefit is a much greater motivator, rather than the nebulous concept of risk,” said Dr. Ference. “So if we begin to crystallize and give an estimate of how much someone can benefit – either from adhering to a healthy lifestyle, with specific goals for LDL and blood pressure reductions, or from encouraging them to remain compliant with their therapies, achieving those corresponding goals – we can quantify their expected clinical benefit and encourage them to invest in their health over the long term.”

Dr. Ference said that the actual mechanism by which lipids and blood pressure are lowered matters less than the amount and duration of lowering: “These data are really agnostic as to the mechanism by which either blood pressure or LDL – or apo-B–containing lipoproteins generally – and blood pressure are reduced. It really suggests that whatever mechanism by which an individual person can most effectively lower their LDL and blood pressure, that’s the best one for that person, if they can maintain that over time.”

Dr. Ference reported financial relationships, including research contracts, consulting arrangements, receipt of royalties, and being an owner or stockholder of more than a dozen pharmaceutical companies. The study was funded by the United Kingdom’s National Institute of Health Research and Medical Research Council, and by the British Heart Foundation.

koakes@mdedge.com

SOURCE: Ference B. et al. ESC Congress 2019, Hot Line Session 3.

PARIS – Over the course of years and decades, lower LDL cholesterol levels and lower systolic blood pressure can reduce the lifetime risk of cardiovascular disease by up to 80%, according to a new study.

SilverV/thinkstockphotos

“What we found is that lifetime exposure to the combination of lower LDL and lower systolic blood pressure is associated with independent, additive, and dose-dependent effects on the lifetime risk of cardiovascular disease,” said the study’s senior author, Brian Ference, MD, speaking at the annual congress of the European Society of Cardiology. “The data seem to confirm that most cardiovascular events are preventable, and suggest that most cardiovascular events can be prevented, with prolonged exposure to modestly lower LDL cholesterol and systolic blood pressure.”

Any reduction of LDL-C and systolic blood pressure (SBP), in any combination, was associated with a lower lifetime risk of cardiovascular disease (CVD) in the study, which took advantage of the United Kingdom’s large Biobank to identify individuals with genetically lower LDL-C and blood pressure levels. The relationship was dose-dependent and showed a log-linear relationship to the combined absolute LDL-C and SBP differences, said Dr. Ference, professor and executive director of the Centre for Naturally Randomised Trials at the University of Cambridge, England.

The results validate current guidelines that focus on a lifetime approach to cardiovascular risk reduction and support a focus on therapeutic lifestyle interventions for individuals at all levels of risk for cardiovascular events, said Dr. Ference. He foresees the results shaping new risk-estimating algorithms and informing the next round of prevention guidelines.

Previous studies had suggested that long-term exposure to lower levels of LDL-C and lower systolic blood pressure reduced cardiovascular risk, but the association hadn’t been fully quantified. Ideally, said Dr. Ference, the question would be answered by a long-term randomized controlled trial, but it would be decades before meaningful data would accrue, and such a trial is unlikely to be conducted.

Using data from 438,952 Biobank participants, Dr. Ference and coinvestigators sought to quantify the association between LDL-C, systolic blood pressure, and atherosclerotic CVD. Taking advantage of genetic variants known to be associated with both lower LDL-C and lower systolic blood pressure, the researchers constructed a “natural randomization” trial. This trial design is also known as Mendelian randomization.

First, the entire study population was randomized into those with exome variants associated with higher or lower LDL-C, which resulted in a mean 15-mg/dL difference between the arms. Then, each LDL-C arm was randomized into groups with exome variants associated with higher or lower SBP, resulting in a difference of 2.9-3 mm Hg between the blood pressure arms within each LDL arm. This randomization yielded a reference group, a group with lower LDL-C, a group with lower SBP, and a group with lower LDL-C and SBP.

For the total population, the mean LDL-C was 138 mg/dL, and the mean SBP was 137.8 mm Hg.

A total of 24,980 participants had coronary revascularization, a nonfatal myocardial infarction (MI), or coronary death – the composite primary outcome measure of major coronary events.

“What we found is that long-term exposure to the combination of 1 mmol/L [about 39 mg/dL] lower LDL and 10 mm/Hg lower blood pressure is associated with an 80% lifetime reduction in risk of cardiovascular events, a 75% reduction in the risk of MI, and 68% reduction in the long-term risk of cardiovascular death,” said Dr. Ference.

By breaking participants out into separate quartiles of LDL-C and SBP levels, and examining outcomes for each quartile independently, Dr. Ference and collaborators were able to ascertain that the salutary effects of lower LDL-C and SBP were independent of each other.

Looking at individual cardiovascular outcomes, “The effect of combined exposure to both lower LDL and lower systolic blood pressure appear to be quite similar across multiple composite cardiovascular outcomes,” said Dr. Ference; benefit was seen in risk of MI, stroke, and other vascular events.

Plotting out the amount of risk reduction against the genetic scores for LDL-C and SBP reduction showed a proportional relationship that was logarithmically linear. “These large proportional reductions in risk really suggest that, for LDL, systolic blood pressure, and their combination, the benefit really depends both on the magnitude and the duration of the exposure,” said Dr. Ference. The effect was seen regardless of age, gender, body mass index, and diabetes status; being a smoker slightly attenuated the effects of LDL-C and SBP.

The mean participant age was 65 years, and women made up 54% of the study population. Aside from lipid values and systolic blood pressure, there were no significant between-group differences.

From these findings, what message can clinicians take to their patients? “Benefit is a much greater motivator, rather than the nebulous concept of risk,” said Dr. Ference. “So if we begin to crystallize and give an estimate of how much someone can benefit – either from adhering to a healthy lifestyle, with specific goals for LDL and blood pressure reductions, or from encouraging them to remain compliant with their therapies, achieving those corresponding goals – we can quantify their expected clinical benefit and encourage them to invest in their health over the long term.”

Dr. Ference said that the actual mechanism by which lipids and blood pressure are lowered matters less than the amount and duration of lowering: “These data are really agnostic as to the mechanism by which either blood pressure or LDL – or apo-B–containing lipoproteins generally – and blood pressure are reduced. It really suggests that whatever mechanism by which an individual person can most effectively lower their LDL and blood pressure, that’s the best one for that person, if they can maintain that over time.”

Dr. Ference reported financial relationships, including research contracts, consulting arrangements, receipt of royalties, and being an owner or stockholder of more than a dozen pharmaceutical companies. The study was funded by the United Kingdom’s National Institute of Health Research and Medical Research Council, and by the British Heart Foundation.

koakes@mdedge.com

SOURCE: Ference B. et al. ESC Congress 2019, Hot Line Session 3.

PARIS – Arguably one of the most important and far-reaching studies presented at the annual congress of the European Society of Cardiology didn’t take place in the massive main ballroom with dazzling lights and sound and thousands of cardiologists in attendance, but in a tiny, makeshift, open-sided venue slapped together of cardboard and fiberboard and plunked down in the noisy poster hall.

Bruce Jancin/MDedge News

It was there that Terence Dwyer, MBBS, MD, began by observing, “We know quite a bit about the relationship of cardiovascular risk factors in adults to cardiovascular disease; we know virtually nothing about the relationship of those risk factors in childhood because – until now – there has been no direct evidence relating to this. What I’m going to present to you is some direct evidence.”

The data come from the International Childhood Cardiovascular Cohort (i3C) Consortium, which includes investigators from seven pioneering prospective child cohort studies, which collectively measured major cardiovascular risk factors in more than 42,000 children beginning back in the 1970s.

Some of these studies will be familiar names to many American physicians and epidemiologists. They include the Bogolusa Heart Study, the Muscatine Study, the Princeton Lipid Research Clinic Study, and the Minneapolis Childhood Cohort Studies. Similar studies were launched decades ago in Australia and Finland. The oldest of these cohorts are now in their 50s, and they are developing cardiovascular disease. The new i3C findings based on pooled data from these studies provides the first direct evidence that high serum cholesterol, blood pressure, body mass index, and smoking in childhood are linked to increased risk of hospitalization for acute MI, stroke, and peripheral artery disease in early middle age, said Dr. Dwyer, emeritus professor of epidemiology at the University of Oxford (England).

The analysis showed that each 10% increase above average in serum cholesterol in childhood was associated with a 16% increased risk of hospitalization for a cardiovascular event at a mean age of 49 years. A 2-point rise in BMI was associated with a 20% higher risk. A 10% increase above average in systolic blood pressure in childhood was linked to a 40% increase in risk of a cardiovascular event in later life. And smoking in childhood or adolescence was associated with a 77% higher risk of a cardiovascular event.

The i3C analysis also demonstrated that exposure to cardiovascular risk factors in childhood has an adverse effect above and beyond that seen when the same risk factors are present only in adulthood. For example, individuals who both as adults and children had two or more of the four major cardiovascular risk factors studied had a sixfold greater risk of a major cardiovascular event in early middle age than if they had two or more risk factors as adults but none as children. If they had two or more risk factors as adults and one risk factor in childhood, their risk of a cardiovascular event was roughly twice as great as if they had no risk factors as a child. And if they had two or more risk factors present in childhood but none in adulthood, their risk of an event was threefold higher than if none of the four major cardiovascular risk factors were present during both periods of life, he continued.

The investigators consider their findings preliminary because most participants in the cohort studies are just reaching age 50 years.

“As we follow them for another 5 years, because of their age, the number of cardiovascular events will increase dramatically,” Dr. Dwyer explained. “One of the reasons we’re presenting this data now in preliminary form is these cohort studies will be the only data of this kind for about another 20 years. We want it out there when it can be most useful. It’s not like the situation with RCTs [randomized, controlled trials] where you’re able to wait 2 years for the next RCT.”

Clinical and policy implications

Asked about the clinical implications of the i3C findings, he replied, “At the very least, at this stage, consideration should be given to lowering risk factors in childhood as a greater priority in the cardiovascular disease prevention field.”

From my experience on national committees that look at what we do about cardiovascular prevention in childhood, they generally say we’re unprepared to take a strong stance on this because we have no direct evidence that these risk factors and what underpins them are a genuine problem,” according to Dr. Dwyer.

That’s no longer the case. By the end of the year, the i3C investigators expect to publish their results. As word reaches the public, he expects to finally see a growing momentum for cardiovascular prevention in pediatrics.

“Just imagine saying to a parent, ‘It looks highly likely that if you don’t do anything about the weight your children have put on, or other risk factors, they will be left at the end of childhood with a residual risk for cardiovascular disease that it doesn’t appear can be completely eradicated. It can be reduced by interventions in adulthood, but something’s happened there in childhood that was important.’ I think parents will demand action at that time,” he said.

Bruce Jancin/MDedge News

In an interview, Donald Lloyd-Jones, MD, called the i3C data “incredibly important.”

“The risk factor values that they’re looking at in kids are not abnormal, they’re at the higher range of what we consider very normal, and yet those slightly elevated exposures within the normal range are causing damage. These kids are accruing risk for atherosclerosis down the road, even within what’s considered to be normal ranges,” commented Dr. Lloyd-Jones, senior associate dean for clinical and translational research and chair of the department of preventive medicine at Northwestern University, Chicago.

“I think it’s very telling that, early in life, we can delineate trajectories already emerging about how these kids are going to play out the rest of their lives in terms of their atherosclerosis and cardiovascular risk. That’s a very important thing to recognize, and we haven’t always thought that way. We always thought you arrive at your 21st birthday and then things start to matter, and by the time you got to 50, now it really matters. But the truth is the horse is already well out of the barn at age 50 and it’s coming out of the barn at age 21. That’s what the i3C data are starting to tell us: that it’s incredibly important that we move further upstream,” the cardiologist added.

What’s the best way forward?

“We have to create an environment where we tilt the playing field towards healthy choices. Sometimes that means taxation policy: It worked for alcohol and tobacco. Sometimes that means frank prohibition: indoor smoking laws have had a huge beneficial effect on public health. Sometimes it’s more controversial, like taxes on sugar-sweetened beverages, but I think that’s an experiment we have to play out to see if it works,” according to Dr. Lloyd-Jones. “I think our best solutions are going to come through policy, environmental change, and lifestyle in the early years because it’s just not practical to think about introducing foreign substances to mass amounts of kids.”

He noted that the National Heart, Lung and Blood Institute has held two workshops within the past year focused on these very issues.

Dr. Lloyd-Jones, past-honored as the American Heart Association Physician of the Year in recognition of his decades of work with that organization in advancing cardiovascular prevention, said “there’s a very good chance” the AHA will take on a major role in what he anticipates will be a much greater emphasis on cardiovascular prevention starting in early life in order to favorably alter life trajectories.

“Stay tuned in the next few months. We’re coming to a decade change, so as we enter 2020, the AHA will be promulgating its strategic goals for the next decade. The AHA is a much bigger, better-funded organization than it was even 10 years ago, and they’re looking to partner with groups like the Robert Woods Johnson Foundation, the Centers for Disease Control, [and] the NIH, to actually make major policy initiatives on cardiovascular prevention,” he said.

The i3C study was funded by the National Heart, Lung, and Blood Institute. Dr. Dwyer reported having no financial conflicts of interest.

bjancin@mdedge.com

PARIS – Arguably one of the most important and far-reaching studies presented at the annual congress of the European Society of Cardiology didn’t take place in the massive main ballroom with dazzling lights and sound and thousands of cardiologists in attendance, but in a tiny, makeshift, open-sided venue slapped together of cardboard and fiberboard and plunked down in the noisy poster hall.

Bruce Jancin/MDedge News

It was there that Terence Dwyer, MBBS, MD, began by observing, “We know quite a bit about the relationship of cardiovascular risk factors in adults to cardiovascular disease; we know virtually nothing about the relationship of those risk factors in childhood because – until now – there has been no direct evidence relating to this. What I’m going to present to you is some direct evidence.”

The data come from the International Childhood Cardiovascular Cohort (i3C) Consortium, which includes investigators from seven pioneering prospective child cohort studies, which collectively measured major cardiovascular risk factors in more than 42,000 children beginning back in the 1970s.

Some of these studies will be familiar names to many American physicians and epidemiologists. They include the Bogolusa Heart Study, the Muscatine Study, the Princeton Lipid Research Clinic Study, and the Minneapolis Childhood Cohort Studies. Similar studies were launched decades ago in Australia and Finland. The oldest of these cohorts are now in their 50s, and they are developing cardiovascular disease. The new i3C findings based on pooled data from these studies provides the first direct evidence that high serum cholesterol, blood pressure, body mass index, and smoking in childhood are linked to increased risk of hospitalization for acute MI, stroke, and peripheral artery disease in early middle age, said Dr. Dwyer, emeritus professor of epidemiology at the University of Oxford (England).

The analysis showed that each 10% increase above average in serum cholesterol in childhood was associated with a 16% increased risk of hospitalization for a cardiovascular event at a mean age of 49 years. A 2-point rise in BMI was associated with a 20% higher risk. A 10% increase above average in systolic blood pressure in childhood was linked to a 40% increase in risk of a cardiovascular event in later life. And smoking in childhood or adolescence was associated with a 77% higher risk of a cardiovascular event.

The i3C analysis also demonstrated that exposure to cardiovascular risk factors in childhood has an adverse effect above and beyond that seen when the same risk factors are present only in adulthood. For example, individuals who both as adults and children had two or more of the four major cardiovascular risk factors studied had a sixfold greater risk of a major cardiovascular event in early middle age than if they had two or more risk factors as adults but none as children. If they had two or more risk factors as adults and one risk factor in childhood, their risk of a cardiovascular event was roughly twice as great as if they had no risk factors as a child. And if they had two or more risk factors present in childhood but none in adulthood, their risk of an event was threefold higher than if none of the four major cardiovascular risk factors were present during both periods of life, he continued.

The investigators consider their findings preliminary because most participants in the cohort studies are just reaching age 50 years.

“As we follow them for another 5 years, because of their age, the number of cardiovascular events will increase dramatically,” Dr. Dwyer explained. “One of the reasons we’re presenting this data now in preliminary form is these cohort studies will be the only data of this kind for about another 20 years. We want it out there when it can be most useful. It’s not like the situation with RCTs [randomized, controlled trials] where you’re able to wait 2 years for the next RCT.”

Clinical and policy implications

Asked about the clinical implications of the i3C findings, he replied, “At the very least, at this stage, consideration should be given to lowering risk factors in childhood as a greater priority in the cardiovascular disease prevention field.”

From my experience on national committees that look at what we do about cardiovascular prevention in childhood, they generally say we’re unprepared to take a strong stance on this because we have no direct evidence that these risk factors and what underpins them are a genuine problem,” according to Dr. Dwyer.

That’s no longer the case. By the end of the year, the i3C investigators expect to publish their results. As word reaches the public, he expects to finally see a growing momentum for cardiovascular prevention in pediatrics.

“Just imagine saying to a parent, ‘It looks highly likely that if you don’t do anything about the weight your children have put on, or other risk factors, they will be left at the end of childhood with a residual risk for cardiovascular disease that it doesn’t appear can be completely eradicated. It can be reduced by interventions in adulthood, but something’s happened there in childhood that was important.’ I think parents will demand action at that time,” he said.

Bruce Jancin/MDedge News

In an interview, Donald Lloyd-Jones, MD, called the i3C data “incredibly important.”

“The risk factor values that they’re looking at in kids are not abnormal, they’re at the higher range of what we consider very normal, and yet those slightly elevated exposures within the normal range are causing damage. These kids are accruing risk for atherosclerosis down the road, even within what’s considered to be normal ranges,” commented Dr. Lloyd-Jones, senior associate dean for clinical and translational research and chair of the department of preventive medicine at Northwestern University, Chicago.

“I think it’s very telling that, early in life, we can delineate trajectories already emerging about how these kids are going to play out the rest of their lives in terms of their atherosclerosis and cardiovascular risk. That’s a very important thing to recognize, and we haven’t always thought that way. We always thought you arrive at your 21st birthday and then things start to matter, and by the time you got to 50, now it really matters. But the truth is the horse is already well out of the barn at age 50 and it’s coming out of the barn at age 21. That’s what the i3C data are starting to tell us: that it’s incredibly important that we move further upstream,” the cardiologist added.

What’s the best way forward?

“We have to create an environment where we tilt the playing field towards healthy choices. Sometimes that means taxation policy: It worked for alcohol and tobacco. Sometimes that means frank prohibition: indoor smoking laws have had a huge beneficial effect on public health. Sometimes it’s more controversial, like taxes on sugar-sweetened beverages, but I think that’s an experiment we have to play out to see if it works,” according to Dr. Lloyd-Jones. “I think our best solutions are going to come through policy, environmental change, and lifestyle in the early years because it’s just not practical to think about introducing foreign substances to mass amounts of kids.”

He noted that the National Heart, Lung and Blood Institute has held two workshops within the past year focused on these very issues.

Dr. Lloyd-Jones, past-honored as the American Heart Association Physician of the Year in recognition of his decades of work with that organization in advancing cardiovascular prevention, said “there’s a very good chance” the AHA will take on a major role in what he anticipates will be a much greater emphasis on cardiovascular prevention starting in early life in order to favorably alter life trajectories.

“Stay tuned in the next few months. We’re coming to a decade change, so as we enter 2020, the AHA will be promulgating its strategic goals for the next decade. The AHA is a much bigger, better-funded organization than it was even 10 years ago, and they’re looking to partner with groups like the Robert Woods Johnson Foundation, the Centers for Disease Control, [and] the NIH, to actually make major policy initiatives on cardiovascular prevention,” he said.

The i3C study was funded by the National Heart, Lung, and Blood Institute. Dr. Dwyer reported having no financial conflicts of interest.

bjancin@mdedge.com

PARIS – Arguably one of the most important and far-reaching studies presented at the annual congress of the European Society of Cardiology didn’t take place in the massive main ballroom with dazzling lights and sound and thousands of cardiologists in attendance, but in a tiny, makeshift, open-sided venue slapped together of cardboard and fiberboard and plunked down in the noisy poster hall.

Bruce Jancin/MDedge News

It was there that Terence Dwyer, MBBS, MD, began by observing, “We know quite a bit about the relationship of cardiovascular risk factors in adults to cardiovascular disease; we know virtually nothing about the relationship of those risk factors in childhood because – until now – there has been no direct evidence relating to this. What I’m going to present to you is some direct evidence.”

The data come from the International Childhood Cardiovascular Cohort (i3C) Consortium, which includes investigators from seven pioneering prospective child cohort studies, which collectively measured major cardiovascular risk factors in more than 42,000 children beginning back in the 1970s.

Some of these studies will be familiar names to many American physicians and epidemiologists. They include the Bogolusa Heart Study, the Muscatine Study, the Princeton Lipid Research Clinic Study, and the Minneapolis Childhood Cohort Studies. Similar studies were launched decades ago in Australia and Finland. The oldest of these cohorts are now in their 50s, and they are developing cardiovascular disease. The new i3C findings based on pooled data from these studies provides the first direct evidence that high serum cholesterol, blood pressure, body mass index, and smoking in childhood are linked to increased risk of hospitalization for acute MI, stroke, and peripheral artery disease in early middle age, said Dr. Dwyer, emeritus professor of epidemiology at the University of Oxford (England).

The analysis showed that each 10% increase above average in serum cholesterol in childhood was associated with a 16% increased risk of hospitalization for a cardiovascular event at a mean age of 49 years. A 2-point rise in BMI was associated with a 20% higher risk. A 10% increase above average in systolic blood pressure in childhood was linked to a 40% increase in risk of a cardiovascular event in later life. And smoking in childhood or adolescence was associated with a 77% higher risk of a cardiovascular event.

The i3C analysis also demonstrated that exposure to cardiovascular risk factors in childhood has an adverse effect above and beyond that seen when the same risk factors are present only in adulthood. For example, individuals who both as adults and children had two or more of the four major cardiovascular risk factors studied had a sixfold greater risk of a major cardiovascular event in early middle age than if they had two or more risk factors as adults but none as children. If they had two or more risk factors as adults and one risk factor in childhood, their risk of a cardiovascular event was roughly twice as great as if they had no risk factors as a child. And if they had two or more risk factors present in childhood but none in adulthood, their risk of an event was threefold higher than if none of the four major cardiovascular risk factors were present during both periods of life, he continued.

The investigators consider their findings preliminary because most participants in the cohort studies are just reaching age 50 years.

“As we follow them for another 5 years, because of their age, the number of cardiovascular events will increase dramatically,” Dr. Dwyer explained. “One of the reasons we’re presenting this data now in preliminary form is these cohort studies will be the only data of this kind for about another 20 years. We want it out there when it can be most useful. It’s not like the situation with RCTs [randomized, controlled trials] where you’re able to wait 2 years for the next RCT.”

Clinical and policy implications

Asked about the clinical implications of the i3C findings, he replied, “At the very least, at this stage, consideration should be given to lowering risk factors in childhood as a greater priority in the cardiovascular disease prevention field.”

From my experience on national committees that look at what we do about cardiovascular prevention in childhood, they generally say we’re unprepared to take a strong stance on this because we have no direct evidence that these risk factors and what underpins them are a genuine problem,” according to Dr. Dwyer.

That’s no longer the case. By the end of the year, the i3C investigators expect to publish their results. As word reaches the public, he expects to finally see a growing momentum for cardiovascular prevention in pediatrics.

“Just imagine saying to a parent, ‘It looks highly likely that if you don’t do anything about the weight your children have put on, or other risk factors, they will be left at the end of childhood with a residual risk for cardiovascular disease that it doesn’t appear can be completely eradicated. It can be reduced by interventions in adulthood, but something’s happened there in childhood that was important.’ I think parents will demand action at that time,” he said.

Bruce Jancin/MDedge News

In an interview, Donald Lloyd-Jones, MD, called the i3C data “incredibly important.”

“The risk factor values that they’re looking at in kids are not abnormal, they’re at the higher range of what we consider very normal, and yet those slightly elevated exposures within the normal range are causing damage. These kids are accruing risk for atherosclerosis down the road, even within what’s considered to be normal ranges,” commented Dr. Lloyd-Jones, senior associate dean for clinical and translational research and chair of the department of preventive medicine at Northwestern University, Chicago.

“I think it’s very telling that, early in life, we can delineate trajectories already emerging about how these kids are going to play out the rest of their lives in terms of their atherosclerosis and cardiovascular risk. That’s a very important thing to recognize, and we haven’t always thought that way. We always thought you arrive at your 21st birthday and then things start to matter, and by the time you got to 50, now it really matters. But the truth is the horse is already well out of the barn at age 50 and it’s coming out of the barn at age 21. That’s what the i3C data are starting to tell us: that it’s incredibly important that we move further upstream,” the cardiologist added.

What’s the best way forward?

“We have to create an environment where we tilt the playing field towards healthy choices. Sometimes that means taxation policy: It worked for alcohol and tobacco. Sometimes that means frank prohibition: indoor smoking laws have had a huge beneficial effect on public health. Sometimes it’s more controversial, like taxes on sugar-sweetened beverages, but I think that’s an experiment we have to play out to see if it works,” according to Dr. Lloyd-Jones. “I think our best solutions are going to come through policy, environmental change, and lifestyle in the early years because it’s just not practical to think about introducing foreign substances to mass amounts of kids.”

He noted that the National Heart, Lung and Blood Institute has held two workshops within the past year focused on these very issues.

Dr. Lloyd-Jones, past-honored as the American Heart Association Physician of the Year in recognition of his decades of work with that organization in advancing cardiovascular prevention, said “there’s a very good chance” the AHA will take on a major role in what he anticipates will be a much greater emphasis on cardiovascular prevention starting in early life in order to favorably alter life trajectories.

“Stay tuned in the next few months. We’re coming to a decade change, so as we enter 2020, the AHA will be promulgating its strategic goals for the next decade. The AHA is a much bigger, better-funded organization than it was even 10 years ago, and they’re looking to partner with groups like the Robert Woods Johnson Foundation, the Centers for Disease Control, [and] the NIH, to actually make major policy initiatives on cardiovascular prevention,” he said.

The i3C study was funded by the National Heart, Lung, and Blood Institute. Dr. Dwyer reported having no financial conflicts of interest.

bjancin@mdedge.com